This is an F1 lobe domain consisting of a ubiquitin like fold found in FERM region of Jak-family tyrosine kinases []. Multidomain JAK molecules interact with receptors through their FERM and SH2-like domains, triggering a series of phosphorylation events, resulting in the activation of their kinase domains []. Overall, the FERM region maintains the typical three-lobed architecture, with an F1 lobe consisting of a ubiquitin-like fold, an F2 lobe consisting of an acyl-CoA binding protein fold, and an F3 lobe consisting of a pleckstrin-homology (PH) fold [].
This is an F2 lobe domain consisting of an acyl-CoA binding protein fold found in FERM region of Jak-family tyrosine kinases []. Multidomain JAK molecules interact with receptors through their FERM and SH2-like domains, triggering a series of phosphorylation events, resulting in the activation of their kinase domains []. Overall, the FERM region maintains the typical three-lobed architecture, with an F1 lobe consisting of a ubiquitin-like fold, an F2 lobe consisting of an acyl-CoA binding protein fold, and an F3 lobe consisting of a pleckstrin-homology (PH) fold. JAK1 FERM-F2 domain has been shown to act as the interaction site for the IFNLR1 box1 motif (PxxLxF) of class II cytokine receptors which is essential for kinase activation [].
This M1 peptidase family includes eukaryotic and bacterial members: aminopeptidase N (APN; MEROPS identifier M01.001), aminopeptidase Q (APQ, laeverin; MEROPS identifier M01.026) [, ], endoplasmic reticulum aminopeptidase 1 (ERAP1; MEROPS identifier M01.018) []as well as tricorn interacting factor F3 (MEROPS identifier M01.021).Aminopeptidase N (APN; CD13; Alanyl aminopeptidase; ), a type II integral membrane protease, consists of a small N-terminal cytoplasmic domain, a single transmembrane domain, and a large extracellular ectodomain that contains the active site. It preferentially cleaves neutral amino acids from the N terminus of oligopeptides and is present in a variety of human tissues and cell types (leukocyte, fibroblast, endothelial and epithelial cells). APN expression is dysregulated in inflammatory diseases such as chronic pain, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, polymyositis/dermatomyosytis and pulmonary sarcoidosis, and is enhanced in tumor cells such as melanoma, renal, prostate, pancreas, colon, gastric and thyroid cancers. It is considered a marker of differentiation since it is predominantly expressed on stem cells and on cells of the granulocytic and monocytic lineages at distinct stages of differentiation. Thus, APN inhibition may lead to the development of anti-cancer and anti-inflammatory drugs [, ].ERAP1 also known as endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP), adipocyte derived leucine aminopeptidase (A-LAP) or aminopeptidase regulating tumor necrosis factor receptor I (THFRI) shedding (ARTS-1), associates with the closely related ER aminopeptidase ERAP2 (MEROPS identifier M01.024), for the final trimming of peptides within the ER for presentation by MHC class I molecules. ERAP1 is associated with ankylosing spondylitis (AS), an inflammatory arthritis that predominantly affects the spine. ERAP1 also aids in the shedding of membrane-bound cytokine receptors [].The tricorn interacting factor F3, together with factors F1 and F2, degrades the tricorn protease products, producing free amino acids, thus completing the proteasomal degradation pathway. F3 is homologous to F2, but not F1, and shows a strong preference for glutamate in the P1' position [].APQ, also known as laeverin, is specifically expressed in human embryo-derived extravillous trophoblasts (EVTs) that invade the uterus during early placentation []. It cleaves the N-terminal amino acid of various peptides such as angiotensin III, endokinin C, and kisspeptin-10, all expressed in the placenta in large quantities.APN is a receptor for coronaviruses, although the virus receptor interaction site seems to be distinct from the enzymatic site and aminopeptidase activity is not necessary for viral infection []. Insect APNs (MEROPS identifiers M01.013 and M01.030) are also putative Cry toxin receptors. Cry1 proteins are pore-forming toxins that bind to the midgut epithelial cell membrane of susceptible insect larvae, causing extensive damage. Several different toxins, including Cry1Aa, Cry1Ab, Cry1Ac, Cry1Ba, Cry1Ca and Cry1Fa, have been shown to bind to APNs; however, a direct role of APN in cytotoxicity has been yet to be firmly established [].
FAK1 (focal adhesion kinase 1) is a non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells. It has been implicated in diverse cellular roles including cell locomotion, mitogen response and cell survival []. The N-terminal region of FAK1 contains a FERM domain, a linker, a kinase domain, and a C-terminal FRNK (FAK-related-non-kinase) domain. Three subdomains of FERM: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3), form a cloverleaf fold, similar to those of known FERM structures despite the low sequence conservation. The phosphoinositide-binding site found in ERM family proteins is not present in the FERM domain of FAK1 []. The adjacent Src SH3 and SH2 binding sites in the linker of FAK1 associates with the F3 and F1 lobes and are thought to be involved in regulation. The FERM domain of FAK1 can inhibit enzymatic activity and repress FAK signaling. In an inactive state of FAK1, the FERM domain is thought to interact with the catalytic domain of FAK1 to repress its activity. Upon activation this interaction is disrupted and its kinase activity restored. The FRNK domain is thought to function as a negative regulator of kinase activity. This entry represents the C-lobe/F3 domain, which is the third structural domain within the FERM domain. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites [, ]. Proteins containing this domain also include protein-tyrosine kinase 2-beta (also known as PYK2), which is a cytoplasmic, non-receptor tyrosine kinase implicated in multiple signaling pathways []. PYK2 is a close paralogue to FAK in vertebrates that can often functionally compensate for loss of FAK [].
Janus kinases (JAKs) are tyrosine kinases that function in membrane-proximal signalling events initiated by a variety of extracellular factors binding to cell surface receptors []. Many type I and II cytokine receptors lack a protein tyrosine kinase domain and rely on JAKs to initiate the cytoplasmic signal transduction cascade. Ligand binding induces oligomerisation of the receptors, which then activates the cytoplasmic receptor-associated JAKs. These subsequently phosphorylate tyrosine residues along the receptor chains with which they are associated. The phosphotyrosine residues are a target for a variety of SH2 domain-containing transducer proteins. Amongst these are the signal transducers and activators of transcription (STAT) proteins, which, after binding to the receptor chains, are phosphorylated by the JAK proteins. Phosphorylation enables the STAT proteins to dimerise and translocate into the nucleus, where they alter the expression of cytokine-regulated genes. This system is known as the JAK-STAT pathway.Four mammalian JAK family members have been identified: JAK1, JAK2, JAK3, and TYK2. They are relatively large kinases of approximately 1150 amino acids, with molecular weights of ~120-130kDa. Their amino acid sequences are characterised by the presence of 7 highly conserved domains, termed JAK homology (JH) domains. The C-terminal domain (JH1) is responsible for the tyrosine kinase function. The next domain in the sequence (JH2) is known as the tyrosine kinase-like domain, as its sequence shows high similarity to functional kinases but does not possess any catalytic activity. Although the function of this domain is not well established, there is some evidence for a regulatory role on the JH1 domain, thus modulating catalytic activity. The N-terminal portion of the JAKs (spanning JH7 to JH3) is important for receptor association and non-catalytic activity, and consists of JH3-JH4, which is homologous to the SH2 domain, and lastly JH5-JH7, which is a FERM domain.The FERM domain has a cloverleaf tripart structure composed of A-lobe or F1, B-lobe or F2, and C-lobe or F3 []. This entry represents the C-lobe/F3 of the FERM domain of JAK2.
