5a63 | pdb_00005a63

Cryo-EM structure of the human gamma-secretase complex at 3.4 angstrom resolution.

Loading... Status: waiting for Mol* initialization Structural highlights 5a63 is a 4 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 4upc. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BMA, NAG, PC1 Gene: NCSTN, KIAA0253, UNQ1874/PRO4317 (HUMAN), PSEN1, AD3, PS1, PSNL1 (HUMAN), APH1A, PSF, CGI-78, UNQ579/PRO1141 (HUMAN), PSENEN, PEN2, MDS033 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [PEN2_HUMAN] Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. [NICA_HUMAN] Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. [PSN1_HUMAN] Defects in PSEN1 are a cause of Alzheimer disease type 3 (AD3) [MIM:607822]. AD3 is a familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. [:] Defects in PSEN1 are a cause of frontotemporal dementia (FTD) [MIM:600274]. Defects in PSEN1 are the cause of cardiomyopathy dilated type 1U (CMD1U) [MIM:613694]. It is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. Defects in PSEN1 are the cause of familial acne inversa type 3 (ACNINV3) [MIM:613737]. A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty. Function [PEN2_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Probably represents the last step of maturation of gamma-secretase, facilitating endoproteolysis of presenilin and conferring gamma-secretase activity. [NICA_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex. [APH1A_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. [PSN1_HUMAN] Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. May also play a role in hematopoiesis. Publication Abstract from PubMed Dysfunction of the intramembrane protease gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human gamma-secretase at 3.4 A resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of gamma-secretase function. An atomic structure of human gamma-secretase.,Bai XC, Yan C, Yang G, Lu P, Ma D, Sun L, Zhou R, Scheres SH, Shi Y Nature. 2015 Aug 17. doi: 10.1038/nature14892. PMID:26280335 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Gamma secretase complex

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