Pleckstrin Homology [PH] domain, structure, mechanism, and contribution to human disease.

Autor: Powis G; PHusis Therapeutics Inc., 6019 Folsom Drive, La Jolla, CA 92037, USA. Electronic address: gpowis20@gmail.com., Meuillet EJ; PHusis Therapeutics Inc., 6019 Folsom Drive, La Jolla, CA 92037, USA., Indarte M; PHusis Therapeutics Inc., 6019 Folsom Drive, La Jolla, CA 92037, USA., Booher G; PHusis Therapeutics Inc., 6019 Folsom Drive, La Jolla, CA 92037, USA., Kirkpatrick L; PHusis Therapeutics Inc., 6019 Folsom Drive, La Jolla, CA 92037, USA.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Sep; Vol. 165, pp. 115024. Date of Electronic Publication: 2023 Jul 01.
DOI: 10.1016/j.biopha.2023.115024
Abstrakt: The pleckstrin homology [PH] domain is a structural fold found in more than 250 proteins making it the 11th most common domain in the human proteome. 25% of family members have more than one PH domain and some PH domains are split by one, or several other, protein domains although still folding to give functioning PH domains. We review mechanisms of PH domain activity, the role PH domain mutation plays in human disease including cancer, hyperproliferation, neurodegeneration, inflammation, and infection, and discuss pharmacotherapeutic approaches to regulate PH domain activity for the treatment of human disease. Almost half PH domain family members bind phosphatidylinositols [PIs] that attach the host protein to cell membranes where they interact with other membrane proteins to give signaling complexes or cytoskeleton scaffold platforms. A PH domain in its native state may fold over other protein domains thereby preventing substrate access to a catalytic site or binding with other proteins. The resulting autoinhibition can be released by PI binding to the PH domain, or by protein phosphorylation thus providing fine tuning of the cellular control of PH domain protein activity. For many years the PH domain was thought to be undruggable until high-resolution structures of human PH domains allowed structure-based design of novel inhibitors that selectively bind the PH domain. Allosteric inhibitors of the Akt1 PH domain have already been tested in cancer patients and for proteus syndrome, with several other PH domain inhibitors in preclinical development for treatment of other human diseases.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are either founders, consultants or work for PHusis Therapeutics and have no other undeclared conflicts of interest that could appear to influence the work reported in this review.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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