| Primary Identifier | IPR003017 | Type | Family |
| Short Name | Amphiphysin_1 |
| description | Amphiphysins belong to the expanding BAR (Bin-Amphiphysin-Rvsp) family proteins, all members of which share a highly conserved N-terminal BAR domain, which has predicted coiled-coil structures required for amphiphysin dimerisation and plasma membrane interaction []. Almost all members also share a conserved C-terminal Src homology 3 (SH3) domain, which mediates their interactions with the GTPase dynamin and the inositol-5'-phosphatase synaptojanin 1 in vertebrates and with actin in yeast. The central region of all these proteins is most variable. In mammals, the central region of amphiphysin I and amphiphysin IIa contains a proline-arginine-rich region for endophilin binding and a CLAP domain, for binding to clathrin and AP-2. The interactions mediated by both the central and C-terminal domains are believed to be modulated by protein phosphorylation [, ].Amphiphysins are proteins involved in clathrin-mediated endocytosis clathrin-mediated endocytosis, actin function, and signalling pathways [, ].Amphiphysin 1 was first identified in 1992 as a brain protein that was partially-associated with synaptic vesicles. Following its cloning, it was also realised to be a human auto-antigen that is detected in a rare neurological disease, Stiff-Man Syndrome, and also in certain types of cancer []. Amphiphysin 1 senses and facilitates membrane curvature to mediate synaptic vesicles invagination and fission during newly retrieved presynaptic vesicle formation and also acts as a linker protein binding with dynamin, clathrin, Amphiphysin II, and other dephosphins in the clathrin-coated complex. Amphiphysin 1 is cleaved an asparagine endopeptidase (AEP), which generates afragment that increases with aging. This fragment disrupts the normal endocytic function of Amphiphysin 1, leading to synaptic dysfunction, as it activates CDK5 inducing tau hyperphosphorylation. Therefore, Amphiphysin 1 posttranslational modification contributes to pathogenesis of Alzheimer's disease, being the AEP a therapeutic target []. |
