| Structural highlights
Function
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.[1] [2] [3]
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[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lee SF, Shah S, Li H, Yu C, Han W, Yu G. Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J Biol Chem. 2002 Nov 22;277(47):45013-9. Epub 2002 Sep 23. PMID:12297508 doi:http://dx.doi.org/10.1074/jbc.M208164200
- ↑ Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G, Xu H. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem. 2003 Mar 7;278(10):7850-4. Epub 2003 Jan 8. PMID:12522139 doi:http://dx.doi.org/10.1074/jbc.C200648200
- ↑ Marlow L, Canet RM, Haugabook SJ, Hardy JA, Lahiri DK, Sambamurti K. APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity. Biochem Biophys Res Commun. 2003 Jun 6;305(3):502-9. PMID:12763021
- ↑ Bai XC, Yan C, Yang G, Lu P, Ma D, Sun L, Zhou R, Scheres SH, Shi Y. An atomic structure of human gamma-secretase. Nature. 2015 Aug 17. doi: 10.1038/nature14892. PMID:26280335 doi:http://dx.doi.org/10.1038/nature14892
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