8bg9
From Proteopedia
Murine amyloid-beta filaments with the Arctic mutation (E22G) from APP(NL-G-F) mouse brains | ABeta
Structural highlights
FunctionA4_MOUSE Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV (By similarity). The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons (By similarity). Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.[1] Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse beta-amyloid peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also bind GPC1 in lipid rafts (By similarity).[2] The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.[3] N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6) (By similarity).[4] Publication Abstract from PubMedThe Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-beta (Abeta)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo-EM structures of Abeta filaments from the frontal cortex of a previously described case (AbetaPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II Abeta42. When compared to the structures of wild-type Abeta42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Abeta molecules and promote filament formation. A minority of Abeta42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Abeta filaments with the Arctic mutation from mouse knock-in line App(NL-G-F). Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (App(NL-G-F) murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The App(NL-G-F) murine Arctic fold differs from the human Arctic folds, but shares some substructure. Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains.,Yang Y, Zhang W, Murzin AG, Schweighauser M, Huang M, Lovestam S, Peak-Chew SY, Saito T, Saido TC, Macdonald J, Lavenir I, Ghetti B, Graff C, Kumar A, Nordberg A, Goedert M, Scheres SHW Acta Neuropathol. 2023 Mar;145(3):325-333. doi: 10.1007/s00401-022-02533-1. Epub , 2023 Jan 7. PMID:36611124[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Large Structures | Mus musculus | Ghetti B | Goedert M | Graff C | Huang M | Kumar A | Lavenir I | Lovestam SKA | Macdonald J | Murzin AG | Nordber A | Peak-Chew SY | Scheres SHW | Schweighauser M | Yang Y | Zhang WJ
