6idf

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Cryo-EM structure of gamma secretase in complex with a Notch fragment

Structural highlights

6idf 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.
Method:Electron Microscopy, Resolution 2.7Å
Experimental data:Check to display Experimental Data
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Aberrant cleavage of Notch by gamma-secretase leads to several types of cancer, but how gamma-secretase recognizes its substrate remains unknown. Here we report the cryo-electron microscopy structure of human gamma-secretase in complex with a Notch fragment at a resolution of 2.7 A. The transmembrane helix of Notch is surrounded by three transmembrane domains of PS1, and the carboxyl-terminal beta-strand of the Notch fragment forms a beta-sheet with two substrate-induced beta-strands of PS1 on the intracellular side. Formation of the hybrid beta-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. These features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by gamma-secretase.

Structural basis of Notch recognition by human gamma-secretase.,Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y Nature. 2019 Jan;565(7738):192-197. doi: 10.1038/s41586-018-0813-8. Epub 2018 Dec, 31. PMID:30598546[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human gamma-secretase. Nature. 2019 Jan;565(7738):192-197. doi: 10.1038/s41586-018-0813-8. Epub 2018 Dec, 31. PMID:30598546 doi:http://dx.doi.org/10.1038/s41586-018-0813-8

Contents


6idf, resolution 2.70Å

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