4uis

The cryoEM structure of human gamma-Secretase complex

Loading... Status: waiting for Mol* initialization Structural highlights 4uis is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease NICA_HUMAN Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. Function 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. Publication Abstract from PubMed The four-component intramembrane protease gamma-secretase is intricately linked to the development of Alzheimer's disease. Despite recent structural advances, the transmembrane segments (TMs) of gamma-secretase remain to be specifically assigned. Here we report a 3D structure of human gamma-secretase at 4.32-A resolution, determined by single-particle, electron cryomicroscopy in the presence of digitonin and with a T4 lysozyme fused to the amino terminus of presenilin 1 (PS1). The overall structure of this human gamma-secretase is very similar to that of wild-type gamma-secretase determined in the presence of amphipols. The 20 TMs are unambiguously assigned to the four components, revealing principles of subunit assembly. Within the transmembrane region, PS1 is centrally located, with its amino-terminal fragment (NTF) packing against Pen-2 and its carboxyl-terminal fragment (CTF) interacting with Aph-1. The only TM of nicastrin associates with Aph-1 at the thick end of the TM horseshoe, and the extracellular domain of nicastrin directly binds Pen-2 at the thin end. TM6 and TM7 in PS1, which harbor the catalytic aspartate residues, are located on the convex side of the TM horseshoe. This structure serves as an important framework for understanding the function and mechanism of gamma-secretase. Structural basis of human gamma-secretase assembly.,Sun L, Zhao L, Yang G, Yan C, Zhou R, Zhou X, Xie T, Zhao Y, Wu S, Li X, Shi Y Proc Natl Acad Sci U S A. 2015 May 12;112(19):6003-8. doi:, 10.1073/pnas.1506242112. Epub 2015 Apr 27. PMID:25918421 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Gamma secretase Lysozyme 3D structures

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