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===Background===
===Background===
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Gamma Secretase (GS) is a transmembrane [https://en.wikipedia.org/wiki/Aspartic_protease aspartatic protease]. It catalyzes peptide bond hydrolysis of type I integral membrane proteins such as Notch, amyloid precursor protein (APP), and various other substrates. It recognizes and catalyzes the reaction with its substrate using 3 residue segments. These 3 residue segments give rise to specific cleavage points for each substrate. APP is the primary substrate of focus, and it is cleaved to form amyloid-β peptides (Aβ). This product is important for various neural processes, and it is well known for its implications with [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease (AD).] This has made GS a popular drug target, specifically using gamma secretase inhibitors. However, due to the nature of the enzyme having various neural functions, there are dangerous side effects when it is inhibited.
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Gamma secretase (GS) is a transmembrane [https://en.wikipedia.org/wiki/Aspartic_protease aspartatic protease] that catalyzes peptide bond hydrolysis of type I integral membrane proteins such as Notch, amyloid precursor protein (APP), and various other substrates. Gamma secretase recognizes and catalyzes the cleavage of its substrate into 3 residue segments. Products of APP cleavage include a variety of amyloid-β (Aβ) peptide fragments separated by 3 residues. These Aβ products are connected neurological diseases like [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease (AD)] with varying length peptide products showing different disease symptoms. The connection between gamma secretase and AD has made a popular drug target. Various inhibitors of gamma secretase have been identified but no inhibitors have been clinically approved for treating AD, as the important neurological functions of gamma secretase has led to dangerous side effects upon inhibition.
===Overall Structure===
===Overall Structure===

Revision as of 03:24, 21 April 2020

Gamma Secretase

Human Gamma Secretase. This protease is made up of 4 subunits: NCT (blue), PS1 (green), APH-1 (pink), and PEN2 (yellow). (PDB code: 5FN2)

Drag the structure with the mouse to rotate

References

  1. 1.0 1.1 Yang G, Zhou R, Shi Y. Cryo-EM structures of human gamma-secretase. Curr Opin Struct Biol. 2017 Oct;46:55-64. doi: 10.1016/j.sbi.2017.05.013. Epub, 2017 Jul 17. PMID:28628788 doi:http://dx.doi.org/10.1016/j.sbi.2017.05.013
  2. 2.0 2.1 2.2 2.3 Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human gamma-secretase. Science. 2019 Feb 15;363(6428). pii: science.aaw0930. doi:, 10.1126/science.aaw0930. Epub 2019 Jan 10. PMID:30630874 doi:http://dx.doi.org/10.1126/science.aaw0930
  3. 3.0 3.1 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
  4. 4.0 4.1 Bolduc DM, Montagna DR, Seghers MC, Wolfe MS, Selkoe DJ. The amyloid-beta forming tripeptide cleavage mechanism of gamma-secretase. Elife. 2016 Aug 31;5. doi: 10.7554/eLife.17578. PMID:27580372 doi:http://dx.doi.org/10.7554/eLife.17578
  5. Kumar D, Ganeshpurkar A, Kumar D, Modi G, Gupta SK, Singh SK. Secretase inhibitors for the treatment of Alzheimer's disease: Long road ahead. Eur J Med Chem. 2018 Mar 25;148:436-452. doi: 10.1016/j.ejmech.2018.02.035. Epub , 2018 Feb 15. PMID:29477076 doi:http://dx.doi.org/10.1016/j.ejmech.2018.02.035

Student Contributors

Layla Wisser

Daniel Mulawa

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