Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Sep:105:27-42.
doi: 10.1016/j.semcdb.2020.05.019. Epub 2020 Jun 29.

The substrate repertoire of γ-secretase/presenilin

Gökhan Güner  1 , Stefan F Lichtenthaler  2
Affiliations
Review

The substrate repertoire of γ-secretase/presenilin

Gökhan Güner et al. Semin Cell Dev Biol. 2020 Sep.

Abstract

The intramembrane protease γ-secretase is a hetero-tetrameric protein complex with presenilin as the catalytic subunit and cleaves its membrane protein substrates within their single transmembrane domains. γ-Secretase is well known for its role in Notch signalling and in Alzheimer's disease, where it catalyzes the formation of the pathogenic amyloid β (Aβ) peptide. However, in the 21 years since its discovery many more substrates and substrate candidates of γ-secretase were identified. Although the physiological relevance of the cleavage of many substrates remains to be studied in more detail, the substrates demonstrate a broad role for γ-secretase in embryonic development, adult tissue homeostasis, signal transduction and protein degradation. Consequently, chronic γ-secretase inhibition may cause significant side effects due to inhibition of cleavage of multiple substrates. This review provides a list of 149 γ-secretase substrates identified to date and highlights by which expeirmental approach substrate cleavage was validated. Additionally, the review lists the cleavage sites where they are known and discusses the functional implications of γ-secretase cleavage with a focus on substrates identified in the recent past, such as CHL1, TREM2 and TNFR1. A comparative analysis demonstrates that γ-secretase substrates mostly have a long extracellular domain and require ectodomain shedding before γ-secretase cleavage, but that γ-secretase is also able to cleave naturally short substrates, such as the B cell maturation antigen. Taken together, the list of substrates provides a resource that may help in the future development of drugs inhibiting or modulating γ-secretase activity in a substrate-specific manner.

Keywords: Alzheimer’s disease; CACHD1; Intramembrane proteolysis; TREM2; γ-Secretase.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

MeSH terms

Substances

LinkOut - more resources