This entry represents the C-terminal BACK (BTB and C-terminal Kelch) domain of speckle-type POZ protein (SPOP, also known as HIB homologue 1 or Roadkill homologue 1). This domain contains a pair of α-helices which seem to be conserved among Cul3 adaptors [].SPOP is an adaptor protein that forms a complex with Cul3, cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, and is involved in ubiquitination of BMI1, H2AFY, and the death-associated protein 6 (DAXX) []. The C-terminal BACK domain of SPOP, may be involved in oligomer formation and in recruiting Cul3 (together with the adjacent BTB domain), whereas the N-terminal MATH domain recruits substrates [, ].
Elongin-C is a highly conserved protein found in a variety of multiprotein complexes in human, rat, fly, worm, and yeast cells []. Budding yeast elongin-C homologue, Elc1, forms a complex with Cul3 that is required for Pol II polyubiquitylation and degradation []. Elc1 also plays a role in global genomic repair []. In humans, elongin-C works as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL) [].
This entry represents a group of BTB/POZ domain-containing proteins, such as BACURD1-3 from humans. They act as the substrate-specific adapters of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, which mediates the ubiquitination of RhoA, leading to its degradation by the proteasome []. This entry also includes EAP3 from Arabidopsis. The BTB/POZ domain of EAP3 displays poor conservation of the residues required for CUL3 binding and is not likely to function as an E3 ligase adaptor [].
Root phototropism protein 3 (RPT3), also known as nonphototropic hypocotyl 3 (NPH3), and root phototropism 2 (RPT2) () represent the founding members of a novel plant-specific family []. Three domains define the members of this family: an N-terminal BTB (broad complex, tramtrack, bric a brac) domain (), a centrally located NPH3 domain (), and a C-terminal coiled-coil domain.NPH3 assembles with CUL3 to form a E3 complex that ubiquitinates phototropin 1 (phot1) and modulates phototropic responsiveness [, ]. NPH3 is necessary for root and hypocotyl phototropisms, but not for the regulation of stomata opening or chloroplast relocation []. Coleoptile phototropism protein 1 (CPT1) is a rice orthologue of Arabidopsis NPH3 also required for phototropism []. This entry also includes DOT3 (AT5G10250) that is involved in shoot and primary root growth; DOT3 mutants produce an aberrant parallel venation pattern in juvenile leaves [].
The NRL (for NPH3/RPT2-Like) family is formed by signaling molecules specificto higher plants. Several regions of sequence and predicted structuralconservation define members of the NRL family, with three domains being mostnotable: an N-terminal BTB domain, a centrally located NPH3domain, and a C-terminal coiled coil domain. The function of the NPH3 domainis not yet known [, , , , , , , ].Root phototropism protein 3 (RPT3), also known as nonphototropic hypocotyl 3 (NPH3), and root phototropism 2 (RPT2) () represent the founding members of a novel plant-specific family []. Three domains define the members of this family: an N-terminal BTB (broad complex, tramtrack, bric a brac) domain (), a centrally located NPH3 domain (), and a C-terminal coiled-coil domain.NPH3 assembles with CUL3 to form a E3 complex that ubiquitinates phototropin 1 (phot1) and modulates phototropic responsiveness [, ]. NPH3 is necessary for root and hypocotyl phototropisms, but not for the regulation of stomata opening or chloroplast relocation []. Coleoptile phototropism protein 1 (CPT1) is a rice orthologue of Arabidopsis NPH3 also required for phototropism []. This entry also includes DOT3 (AT5G10250) that is involved in shoot and primary root growth; DOT3 mutants produce an aberrant parallel venation pattern in juvenile leaves [].
This entry includes SKP1 and SKP1-like protein, elongin-C (also known as TCEB1). SKP1 is part of the E3 ubiquitin ligase complexes. Elongin-C has dual functions, works as a component of RNA polymerase II (Pol II) transcription elongation factor and as the substrate recognition subunit of a Cullin-RING E3 ubiquitin ligase []. Mammlian S-phase kinase-associated protein 1 (SKP1) is an essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription []. It is also part of the ubiquitin E3 ligase complex (Skp1-Pam-Fbxo45) that controls the core epithelial-to-mesenchymal transition-inducing transcription factors []. Budding yeast Skp1 is a kinetochore protein found in several complexes, including the SCF ubiquitin ligase complex, the CBF3 complex that binds centromeric DNA [], and the RAVE complex that regulates assembly of the V-ATPase []. Elongin-C is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites []. It forms a complex with SIII regulatory subunits B, which serves as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes []. Elongin-C forms a complex with Cul3 that polyubiquitylates monoubiquitylated RNA polymerase II to trigger its proteolysis [].
Kelch-like protein 17 (KLHL17, also known as actinfilin) and Kelch-like protein 20 (KLHL20, also known as KLEIP) belong to the KLHL family []. KLHL17 binds to the actin cytoskeleton and serves as a substrate-specific adapter in the Cul3-dependent ubiquitin ligase complex that targets GluR6 kainate receptor subunit for degradation []. Kainate receptors (KAR) are ionotropic receptors that respond to the neurotransmitter glutamate and have been implicated in epilepsy, stroke, Alzheimer's and neuropathic pain [].KLHL20 assembles with CUL3 and RBX1 to form a multi-subunit Cullin-RING E3 ligase []. The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding [], while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins []. In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins []. Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases [, ].
Kelch-like protein 21 (KLHL21) is a substrate adaptor protein in the Cul3-KLHL21 E3 ubiquitin ligase complex. During cytokinesis, it localises to midzone microtubules in anaphase and recruits aurora B and Cul3 to this region [].The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding [], while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins []. In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins []. Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases [, ].
TAZ (Transcription Adaptor putative Zinc finger) domains are zinc-containing domains found in the homologous transcriptional co-activators CREB-binding protein (CBP) and the P300. CBP and P300 are histone acetyltransferases () that catalyse the reversible acetylation of all four histones in nucleosomes, acting to regulate transcription via chromatin remodelling. These large nuclear proteins interact with numerous transcription factors and viral oncoproteins, including p53 tumour suppressor protein, E1A oncoprotein, MyoD, and GATA-1, and are involved in cell growth, differentiation and apoptosis []. Both CBP and P300 have two copies of the TAZ domain, one in the N-terminal region, the other in the C-terminal region. The TAZ1 domain of CBP and P300 forms a complex with CITED2 (CBP/P300-interacting transactivator with ED-rich tail), inhibiting the activity of the hypoxia inducible factor (HIF-1alpha) and thereby attenuating the cellular response to low tissue oxygen concentration []. Adaptation to hypoxia is mediated by transactivation of hypoxia-responsive genes by hypoxia-inducible factor-1 (HIF-1) in complex with the CBP and p300 transcriptional coactivators [].Proteins containing this domain also include a group of land-plant specific proteins, know as the BTB/POZ and TAZ domain-containing (BT) protein. The reports of their interaction with CUL3 are contradictory. They are multifunctional scaffold proteins essential for male and female gametophyte development []. The TAZ domain adopts an all-alpha fold with zinc-binding sites in the loops connecting the helices. The TAZ1 domain in P300 and the TAZ2 (CH3) domain in CBP have each been shown to have four amphipathic helices, organised by three zinc-binding clusters with HCCC-type coordination [, , ].
TAZ (Transcription Adaptor putative Zinc finger) domains are zinc-containing domains found in the homologous transcriptional co-activators CREB-binding protein (CBP) and the P300. CBP and P300 are histone acetyltransferases () that catalyse the reversible acetylation of all four histones in nucleosomes, acting to regulate transcription via chromatin remodelling. These large nuclear proteins interact with numerous transcription factors and viral oncoproteins, including p53 tumour suppressor protein, E1A oncoprotein, MyoD, and GATA-1, and are involved in cell growth, differentiation and apoptosis []. Both CBP and P300 have two copies of the TAZ domain, one in the N-terminal region, the other in the C-terminal region. The TAZ1 domain of CBP and P300 forms a complex with CITED2 (CBP/P300-interacting transactivator with ED-rich tail), inhibiting the activity of the hypoxia inducible factor (HIF-1alpha) and thereby attenuating the cellular response to low tissue oxygen concentration []. Adaptation to hypoxia is mediated by transactivation of hypoxia-responsive genes by hypoxia-inducible factor-1 (HIF-1) in complex with the CBP and p300 transcriptional coactivators [].Proteins containing this domain also include a group of land-plant specific proteins, know as the BTB/POZ and TAZ domain-containing (BT) protein. The reports of their interaction with CUL3 are contradictory. They are multifunctional scaffold proteins essential for male and female gametophyte development []. The TAZ domain adopts an all-alpha fold with zinc-binding sites in the loops connecting the helices. The TAZ1 domain in P300 and the TAZ2 (CH3) domain in CBP have each been shown to have four amphipathic helices, organised by three zinc-binding clusters with HCCC-type coordination [, , ].Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [, , , , ]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures andthe number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few []. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
