Amyloid-beta precursor protein, also known as amyloid beta A4 protein (APP or A4), consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. There are several alternative splicing isoforms of APP in humans. Two of the main isoforms, amyloid-β40 (Abeta40) and amyloid-β42 (Abeta42), are found predominantly in the extracellular brain deposits associated with Alzheimer's disease (AD) []. The ratio of Abeta42 to Abeta40 affects the pathogenesis of AD []. The Abeta peptide is mostly unstructured, and through molecular dynamics simulations, confirmed by amyloid-oligomer-specific antibodies, was revealed that Abeta monomer acquires the atypical alpha-sheet secondary structure that adopts an alpha-strand structure which proceeds to an alpha-sheet between adjacent alpha-strands in oligomers with opposite charges on both edges, inducing self-assembly/aggregation to form soluble oligomeric amyloid protofibrils and finally, insoluble highly ordered amyloid fibrils with a cross β-sheet structure [, , ].APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.
This family includes calsyntenin 1/2/3 (also known as alcadein-alpha/beta/gamma). They are single-pass type I membrane proteins that may modulate calcium-mediated postsynaptic signals [].CLSTN (also known as Alc) forms a tripartite complex with APP (amyloid beta-protein precursor) and X11L (a neuron-specific adaptor protein) in brain; this complex stabilizes both APP and CLSTN proteins metabolically. Deficiencies in the X11L-mediated interaction between CLSTN and APP and/or CTFbeta enhances the production of amyloid beta-protein and have been linked to the development or progression of Alzheimer's disease []. Moreover, CLSTN1 strongly associates with kinesin-1 light chains (KLC1) and acts as a cargo that regulates kinesin-1 function. It may affect the transport of APP-containing vesicles by kinesin-1 [].
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This entry represents the family of amyloidogenic glycoproteins, such as amyloid-beta precursor protein (APP, or A4) and amyloid beta precursor like protein 1/2 (APLP1/2). APP is an integral, glycosylated membrane protein.
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This superfamily represents a heparin-binding domain found at the N-terminal of the extracellular domain, which is itself found at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4). The core of the heparin-binding domain has an unusual disulphide-rich fold, consisting of a beta-x-α-β-loop-beta topology [].
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This superfamily represents a copper-binding domain found within the extracellular domain, which is at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4). The copper-binding domain has a dodecin-like fold consisting of a 2-layer alpha/beta topology [].
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transportof beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This entry represents a conserved octapeptide located in the CuBD domain.
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This entry represents a conserved signature pattern located in the intra-cellular domain and found towards the C-terminal extremity of these proteins.
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This entry represents the amyloid-beta peptide (A-beta) superfamily, which originates as a breakdown product from the cleavage of amyloid-beta precursor protein (APP, or A4), an integral, glycosylated membrane brain protein.
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This entry represents a heparin-binding domain found at the N-terminal of the extracellular domain, which is itself found at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4). The core of the heparin-binding domain has an unusual disulphide-rich fold, consisting of a beta-x-α-β-loop-beta topology [].
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This entry represents the amyloid-beta peptide (A-beta), which originates as a breakdown product from the cleavage of amyloid-beta precursor protein (APP, or A4), an integral, glycosylated membrane brain protein.
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This entry represents a copper-binding domain found within the extracellular domain, which is at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4). The copper-binding domain has a dodecin-like fold consisting of a 2-layer alpha/beta topology [].
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cellsurface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.This entry represents an extracellular domain that is usually found at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4).
This entry represents the cytoplasmic C-terminal domain of calsyntenin (CLSTN) proteins 1, 2 and 3 (also known as alcadein-alpha, beta and gamma). These are postsynaptic Ca2-binding proteins, evolutionarily conserved type I membrane proteins. CLSTN (also known as Alc) forms a tripartite complex with APP (amyloid beta-protein precursor) and X11L (a neuron-specific adaptor protein) in brain; this complex stabilizes both APP and CLSTN proteins metabolically. Deficiencies in the X11L-mediated interaction between CLSTN and APP and/or CTFbeta enhances the production of amyloid beta-protein and have been linked to the development or progression of Alzheimer's disease []. Moreover, CLSTN1 strongly associates with kinesin-1 light chains (KLC1) and acts as a cargo that regulates kinesin-1 function. It may affect the transport of APP-containing vesicles by kinesin-1 []. This domain includes the WD motifs required for KLC1 interaction (although one WD motif is sufficient), and the NP motif [].
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [, , ]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [, ]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility []. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [, ]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.APP can be processed by different sets of enzymes:In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling). In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.The E2 domain is the largest of the conserved domains in the amyloidogenic glycoproteins. The structure of E2 consists of two coiled-coil sub-structures connected through a continuous helix, and bears an unexpected resemblance to the spectrin family of protein structures. E2 can reversibly dimerise in solution, and the dimerisation occurs along the longest dimension of the molecule in an antiparallel orientation, which enables the N-terminal substructure of one monomer to pack against the C-terminal substructure of a second monomer. The high degree of conservation of residues at the putative dimer interface suggests that the E2 dimer observed in the crystal could be physiologically relevant. Heparin sulphate proteoglycans, the putative ligands for the precursor present in extracellular matrix, bind to E2 at a conserved and positively charged site near the dimer interface []. The E2 domain is also known as CAPPD (for central APP domain) [].
This entry represents the FE65 family, whose members include FE65 (APBB1), FE65L1 (APBB2), and FE65L2 (APBB3). They are adaptor proteins that bind the C-terminal region of the amyloid precursor protein (APP) []. APBB1 is a neuronal adaptor protein involved in brain development, Alzheimer disease amyloid precursor protein (APP) signaling, and proteolytic processing of APP [, ]. It contains three protein-protein interaction domains, one WW domain, and two phosphotyrosine-binding domains (PTBs)[]. The C-terminal Fe65-PTB2 binds a large portion of the APP intracellular domain (AICD) including the GYENPTY internalization sequence fingerprint []. This entry also includes an Fe65 homologue from C. elegans, Feh-1. Besides binding to amyloid precursor protein, it is also involved in the same pathway that controls nematode pharyngeal pumping [].
The beta-site APP cleaving enzyme-1 (BACE1), also known as Aspartyl protease 2 and memapsin-2, mediates one of the two proteolytic cleavages of beta-amyloid precursor protein (APP) to yield the amyloid β-peptide (Abeta), a key pathogenic agent in Alzheimer's disease (AD) []. Axonal and Schwann cell BACE1 is also required for remyelination of injured nerves []. BACE1 inhibitor drugs have been evaluated for AD treatment []. BACE1 is () and MEROPS identifier A01.004.
One of the major neuropathological hallmarks of Alzheimer's disease (AD)is the progressive formation in the brain of insoluble amyloid plaques and vascular deposits consisting of beta-amyloid protein (beta-APP) [].Production of beta-APP requires proteolytic cleavage of the large type-1 transmembrane (TM) protein amyloid precursor protein (APP) []. This processis performed by a variety of enzymes known as secretases. To initiate beta-APP formation, beta-secretase cleaves APP to release a soluble N-terminal fragment (APPsBeta) and a C-terminal fragment that remains membrane bound. This fragment is subsequently cleaved by gamma-secretase to liberate beta-APP.Several independent studies identified a novel TM aspartic protease as themajor beta-secretase [, , ]. This protein, termed beta-site APP cleavingenzyme 1 (BACE1), shares 64% amino acid sequence similarity with a secondenzyme, termed BACE2. Together, BACE1 and BACE2 define a novel family of aspartyl proteases []. Both enzymes share significant sequence similaritywith other members of the pepsin family of aspartyl proteases and contain the two characteristic D(T/S)G(T/S) motifs that form the catalytic site.However, by contrast with other aspartyl proteases, BACE1 and BACE2 aretype I TM proteins. Each protein comprises a large lumenal domain containingthe active centre, a single TM domain and a small cytoplasmic tail.
The E2 domain is the largest of the conserved domains in the amyloidogenic glycoproteins. The structure of E2 consists of two coiled-coil sub-structures connected through a continuous helix, and bears an unexpected resemblance to the spectrin family of protein structures. E2 can reversibly dimerise in solution, and the dimerisation occurs along the longest dimension of the molecule in an antiparallel orientation, which enables the N-terminal substructure of one monomer to pack against the C-terminal substructure of a second monomer. The high degree of conservation of residues at the putative dimer interface suggests that the E2 dimer observed in the crystal could be physiologically relevant. Heparin sulphate proteoglycans, the putative ligands for the precursor present in extracellular matrix, bind to E2 at a conserved and positively charged site near the dimer interface []. The E2 domain is also known as CAPPD (for central APP domain) [].
Prohormone convertases (PCs) 1 and 2 are a family of eukaryotic subtilisins thought to mediate the proteolytic cleavage of many peptide precursors []. Protein 7B2 (secretogranin V) functions as a molecular chaperone for PC2, preventing its premature activation in the regulated secretory pathway []. 7B2 represents a potent inhibitor of PC2, and it is also required for the activation of PC2, which is synthesised as a zymogen. Protein 7B2 has an N-terminalactivation domain and a C-terminal (CT) inhibitory domain (MEROPS inhibitor family I21), separated by a furin cleavage site []. 7B2 is synthesised as a precursor protein that is cleaved into the N-terminal fragment and the C-terminal peptide [].7B2 has been linked to neurodegenerative diseases. It may act as an anti-aggregation chaperone []. However, in an APP model mouse 7B2 knockout has been shown to reduce rather than enhance plaque burden [].
Amyloid beta A4 precursor protein-binding family A member 2, also known as Mint2, X11beta, or X11L, is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP) []. It belongs to the X11/Mint family of adaptor proteins []. It has been shown to modulate processing of APP and accumulation of Abeta (hallmark pathologies of Alzheimer's disease), making it a potential therapeutic target for Alzheimer's disease [, ]. X11beta, as X11alpha, is a important regulator of presynaptic neurotransmitter release [].The X11/Mint family members are multidomain proteins typically composed of a conserved PTB domain and two C-terminal PDZ domains. They are adaptor proteins that possess several functions, such as trafficking and transport, synaptic function and regulation of ion channel []. Two of the family members,X11alpha and X11beta, are expressed primarily in neurones [].
ADAM19 peptidase (also known as meltrin beta; MEROPS identifier M12.214) is located in the Golgi. It sheds the ectodomain of NRG1beta1 from the Golgi membranes []and also sheds other proteins, such as heparin-binding epidermal growth factor, tumour necrosis factor and the amyloid precursor protein (APP) []. Because the peptides released from APP do not form amyloid deposits, ADAM19 may have a protective role in Alzheimer's disease []. ADAM19 is a multidomain protein with a propeptide, a metallopeptidase, a disintegrin, and a cysteine-rich domain, followed by a transmembrane region and a cytoplasmic tail. The propeptide is removed by furin []. The cytoplasmic tail interacts with the SH3 domain of Tks5(I) []. The ADAM19 gene is expressed in muscle and nerve cells during embryonic development and a short isoform is found in dorsal root ganglia []. The gene is also over-expressed in several human cancers and cancer cell lines including astrocytomas and glioblastomas []and in the placenta, where ADAM19 may reduce cell invasion [].
One of the major neuropathological hallmarks of Alzheimer's disease (AD) is the progressive formation in the brain of insoluble amyloid plaques and vascular deposits consisting of beta-amyloid protein (beta-APP) []. Production of beta-APP requires proteolytic cleavage of the large type-1 transmembrane (TM) protein amyloid precursor protein (APP) []. This process is performed by a variety of enzymes known as secretases. To initiate beta-APP formation, beta-secretase cleaves APP to release a soluble N-terminal fragment (APPsBeta) and a C-terminal fragment that remains membrane bound. This fragment is subsequently cleaved by gamma-secretase to liberate beta-APP.Several independent studies identified a novel TM aspartic protease as the major beta-secretase [, , ]. This protein, termed memapsin 2 or beta-site APP cleaving enzyme 1 (BACE1), shares 64% amino acid sequence similarity with a second enzyme, termed BACE2. Together, BACE1 and BACE2 define a novel family of aspartyl proteases []. Both enzymes share significant sequence similarity with other members of the pepsin family of aspartyl proteases and contain the two characteristic D(T/S)G(T/S) motifs that form the catalytic site. However, by contrast with other aspartyl proteases, BACE1 and BACE2 are type I TM proteins. Each protein comprises a large lumenal domain containing the active centre, a single TM domain and a small cytoplasmic tail.BACE2, also termed Asp1 and memapsin 1, was initially identified though Expressed Sequence Tag (EST) database searching. In vitro enzymaticassays with peptide substrates have demonstrated that BACE2 cleaves beta-secretase substrates in a similar fashion to BACE1 []. The BACE2 mRNA is expressed in the central nervous system and many peripheral tissues, although its expression level in neurons is substantially lower than that of BACE1 [].
Amyloid beta A4 precursor protein-binding family A member 1, also known as Mint1 or X11alpha, is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP) []. It belongs to the X11/Mint family of adaptor proteins []. It has been shown to modulate processing of APP and accumulation of Abeta (hallmark pathologies of Alzheimer's disease), making it a potential therapeutic target for Alzheimer's disease []. It may also affect Alzheimer's disease pathogenesis through its interaction with transcription factor FSBP (fibrinogen silencer binding protein), forming a complex that represses glycogen synthase kinase-3beta (GSK3beta) transcription. GSK3beta is a candidate kinase for the phosphorylation of tau in Alzheimer's disease [].X11alpha participates in a brain-specific heterotrimeric complex containing two other PDZ domain proteins, Lin-2/CASK and mLin-7, involved in synaptic vesicle exocytosis and synaptic junctions []. Additional proteins can bind, forming a neuronal multiprotein complex predicted to be involved in receptor localisation []. The X11/Mint family members are multidomain proteins typically composed of a conserved PTB domain and two C-terminal PDZ domains. They are adaptor proteins that possess several functions, such as trafficking and transport, synaptic function and regulation of ion channel []. Two of the family members, X11alpha and X11beta, are expressed primarily in neurones [].
This superfamily represents the C-terminal region of aspartic peptidases belonging to the MEROPS peptidase family A22 (presenilin family), subfamily A22A, the type example being presenilin 1 from Homo sapiens (Human).Presenilins are polytopic transmembrane (TM) proteins, mutations in whichare associated with the occurrence of early-onset familial Alzheimer'sdisease, a rare form of the disease that results from a single-genemutation [, ]. Alzheimer's disease is associated with the formation of extracellular deposits of amyloid, which contain aggregates of the amyloid-beta peptide. The β-peptides are released from the Alzheimer's amyloid precursor protein (APP) by the action of two peptidase activities: "beta-secretase"cleaves at the N terminus of the peptide, and "gamma-secretase"cleaves at the C terminus. The gamma-secretase cleavage occurs in a transmembrane segment of APP. Presenilin, which exists in a complex with nicastrin, APH-1 and PEN-2, has been identified as gamma-secretase from its deficiency []and mutation of its active site residues [], but proteolytic activity has only been directly demonstrated on a peptide derived from APP [].Presenilin-1 is also known to process notch proteins []and syndecan-3 [].Presenilin has nine transmembrane regions with the active site aspartic acid residues located on TM6, within a Tyr-Asp motif, and TM7, within a Gly-Xaa-Gly-Asp motif []. The protein autoprocesses to form an amino-terminal fragment (TMs 1-6) and a C-terminal fragment (TMs 7-9) []. The tertiary structure of the human gamma-sectretase complex has been solved []. Nicastrin is extracellular, whereas presenilin-1, APH-1 and PEN-2 are all transmembrane proteins. The transmembrane regions of all three proteins form a horseshoe shape.
Tumor necrosis factor receptor superfamily member 21 (TNFRSF21), also known as death receptor 6 (DR6), CD358, or BM-018, is highly expressed in differentiating neurons as well as in the adult brain, and is upregulated in injured neurons []. DR6 negatively regulates neuron, axon, and oligodendrocyte survival, hinders axondendrocyte and oligodendrocyte regeneration and its inhibition has a neuro-protective effect in nerve injury []. It activates nuclear factor kappa-B (NFkB) and mitogen-activated protein kinase 8 (MAPK8, also called c-Jun N-terminal kinase 1), and induces cell apoptosis by associating with TNFRSF1A-associated via death domain (TRADD), which is known to mediate signal transduction of tumor necrosis factor receptors []. TNFRSF21 plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation []. It binds alpha-amyloid precursor protein (APP); when released, APP binds in an autocrine/paracrine manner to activate a caspase-dependent self-destruction program that removes unnecessary or connectionless axons []. Increasing beta-catenin levels in brain endothelium upregulates TNFRSF21 and TNFRSF19, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for blood-brain barrier development []. DR6 is up-regulated in numerous solid tumors as well as in tumor vascular cells, including ovarian cancer and may be a clinically useful diagnostic and predictive serum biomarker for some adult sarcoma subtypes [].This entry represents the N-terminal domain of TNFRSF21. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
This entry includes the peptidase domain of aspartic endopeptidases known as memapsins. In humans there are two enzymes, memapsin-1 (also known as BACE2 or beta-site of APP cleaving enzyme 1; MEROPS identifier A01.041) and memapsin-2 (BACE1; MEROPS identifier A01.004).Beta-secretase is an aspartic-acid protease important in the pathogenesis of Alzheimer's disease, and in the formation of myelin sheaths in peripheral nerve cells. It cleaves amyloid precursor protein (APP) to reveal the N terminus of the beta-amyloid peptides. The beta-amyloid peptides are the major components of the amyloid plaques formed in the brain of patients with Alzheimer's disease (AD). Since BACE mediates one of the cleavages responsible for generation of AD, it is regarded as a potential target for pharmacological intervention in AD. Beta-secretase is a member of pepsin family of aspartic proteases (peptidase family A1) [, ].Aspartyl proteases (APs), also known as acid proteases, ([intenz:3.4.23.-]) are a widely distributed family of proteolytic enzymes [, , , , , ]known to exist in vertebrates, fungi, plants, retroviruses and some plant viruses. APs use an Asp dyad to hydrolyze peptide bonds.APs found in eukaryotic cells are alpha/beta monomers composed of two asymmetric lobes ("bilobed"). Each of the lobes provides a catalytic Asp residue, positioned within the hallmark motif Asp-Thr/Ser-Gly, to the active site. The N- and C-terminal domains, although structurally related by a 2-fold axis, have only limited sequence homology except the vicinity of the active site. This suggests that the enzymes evolved by an ancient duplication event. The enzymes specifically cleave bonds in peptides which have at least six residues in length with hydrophobic residues in both the P1 andP1' positions. The active site is located at the groove formed by the two lobes, with an extended loop projecting over the cleft to form an 11-residue flap, which encloses substrates and inhibitors in the active site. Specificity is determined by nearest-neighbour hydrophobic residues surrounding the catalytic aspartates, and by three residues in the flap. The enzymes are mostly secreted from cells as inactive proenzymes that activate autocatalytically at acidic pH. Eukaryotic APs form peptidase family A1 of clan AA.
This group of aspartic peptidases belong to MEROPS peptidase family A22 (presenilin family), subfamily A22A, the type example being presenilin 1 from Homo sapiens (Human).Presenilins are polytopic transmembrane (TM) proteins, mutations in whichare associated with the occurrence of early-onset familial Alzheimer'sdisease, a rare form of the disease that results from a single-genemutation [, ]. Alzheimer's disease is associated with the formation of extracellular deposits of amyloid, which contain aggregates of the amyloid-beta peptide. The β-peptides are released from the Alzheimer's amyloid precursor protein (APP) by the action of two peptidase activities: "beta-secretase"cleaves at the N terminus of the peptide, and "gamma-secretase"cleaves at the C terminus. The gamma-secretase cleavage occurs in a transmembrane segment of APP. Presenilin, which exists in a complex with nicastrin, APH-1 and PEN-2, has been identified as gamma-secretase from its deficiency []and mutation of its active site residues [], but proteolytic activity has only been directly demonstrated on a peptide derived from APP [].Presenilin-1 is also known to process notch proteins []and syndecan-3 [].Presenilin has nine transmembrane regions with the active site aspartic acid residues located on TM6, within a Tyr-Asp motif, and TM7, within a Gly-Xaa-Gly-Asp motif []. The protein autoprocesses to form an amino-terminal fragment (TMs 1-6) and a C-terminal fragment (TMs 7-9) []. The tertiary structure of the human gamma-sectretase complex has been solved []. Nicastrin is extracellular, whereas presenilin-1, APH-1 and PEN-2 are all transmembrane proteins. The transmembrane regions of all three proteins form a horseshoe shape.Aspartic peptidases, also known as aspartyl proteases ([intenz:3.4.23.-]), are widely distributed proteolytic enzymes [, , ]known to exist in vertebrates, fungi, plants, protozoa, bacteria, archaea, retroviruses and some plant viruses. All known aspartic peptidases are endopeptidases. A water molecule, activated by two aspartic acid residues, acts as the nucleophile in catalysis. Aspartic peptidases can be grouped into five clans, each of which shows a unique structural fold [].Peptidases in clan AA are either bilobed (family A1 or the pepsin family) or are a homodimer (all other families in the clan, including retropepsin from HIV-1/AIDS) []. Each lobe consists of a single domain with a closed β-barrel and each lobe contributes one Asp to form the active site. Most peptidases in the clan are inhibited by the naturally occurring small-molecule inhibitor pepstatin [].Clan AC contains the single family A8: the signal peptidase 2 family. Members of the family are found in all bacteria. Signal peptidase 2 processes the premurein precursor, removing the signal peptide. The peptidase has four transmembrane domains and the active site is on the periplasmic side of the cell membrane. Cleavage occurs on the amino side of a cysteine where the thiol group has been substituted by a diacylglyceryl group. Site-directed mutagenesis has identified two essential aspartic acid residues which occur in the motifs GNXXDRX and FNXAD (where X is a hydrophobic residue) []. No tertiary structures have been solved for any member of the family, but because of the intramembrane location, the structure is assumed not to be pepsin-like.Clan AD contains two families of transmembrane endopeptidases: A22 and A24. These are also known as "GXGD peptidases"because of a common GXGD motif which includes one of the pair of catalytic aspartic acid residues. Structures are known for members of both families and show a unique, common fold with up to nine transmembrane regions []. The active site aspartic acids are located within a large cavity in the membrane into which water can gain access [].Clan AE contains two families, A25 and A31. Tertiary structures have been solved for members of both families and show a common fold consisting of an α-β-alpha sandwich, in which the beta sheet is five stranded [, ].Clan AF contains the single family A26. Members of the clan are membrane-proteins with a unique fold. Homologues are known only from bacteria. The structure of omptin (also known as OmpT) shows a cylindrical barrel containing ten beta strands inserted in the membrane with the active site residues on the outer surface [].There are two families of aspartic peptidases for which neither structure nor active site residues are known and these are not assigned to clans. Family A5 includes thermopsin, an endopeptidase found only in thermophilic archaea. Family A36 contains sporulation factor SpoIIGA, which is known to process and activate sigma factor E, one of the transcription factors that controls sporulation in bacteria [].
