Desmoplakin CSM models unravel mechanisms regulating the binding to intermediate filaments and putative therapeutics for cardiocutaneous diseases.

Autor: Badowski C; Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore. cedricb2023@hotmail.com., Benny P; Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore.; Department of Obstetrics and Gynaecology, National University Hospital, National University of Singapore, 1E Kent Ridge Rd, Level 12 NUHS Tower Block, Singapore, 119228, Singapore.; NUS Bia-Echo Asia Centre of Reproductive Longevity and Equality, Yong Loo Lin School of Medicine, National University of Singapore, Immunos Building, 8A Biomedical Grove, Singapore, Singapore., Verma CS; Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, 138671, Singapore., Lane EB; Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore. birgit.lane@sris.a-star.edu.sg.; Skin Research Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Immunos Building, 8A Biomedical Grove, Singapore, 138648, Singapore. birgit.lane@sris.a-star.edu.sg.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Oct 05; Vol. 14 (1), pp. 23206. Date of Electronic Publication: 2024 Oct 05.
DOI: 10.1038/s41598-024-73705-0
Abstrakt: Arrhythmogenic cardiomyopathy (AC) is a common cause of sudden cardiac arrest and death in young adults. It can be induced by different types of mutations throughout the desmoplakin gene including the R2834H mutation in the extreme carboxyterminus tail of desmoplakin (DP CT) which remains structurally uncharacterized and poorly understood. Here, we have created 3D models of DP CT which show the structural effects of AC-inducing mutations as well as the implications of post-translational modifications (PTMs). Our results suggest that, in absence of PTMs, positively charged wildtype DP CT likely folds back onto negatively-charged plectin repeat 14 of nearby plakin repeat domain C (PRD C) contributing to the recruitment of intermediate filaments (IFs). When phosphorylated and methylated, negatively-charged wildtype DP CT would then fold back onto positively-charged plectin repeat 17 of PRD C, promoting the repulsion of intermediate filaments. However, by preventing PTMs, the R2834H mutation would lead to the formation of a cytoplasmic mutant desmoplakin with a constitutively positive DP CT tail that would be aberrantly recruited by cytoplasmic IFs instead of desmosomes, potentially weakening cell-cell contacts and promoting AC. Virtual screening of FDA-approved drug libraries identified several promising drug candidates for the treatment of cardiocutaneous diseases through drug repurposing.
(© 2024. The Author(s).)
Databáze: MEDLINE
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