4.6 Article

Cytochrome C interacts with the pathogenic mutational hotspot region of TRPV4 and forms complexes that differ in mutation and metal ion-sensitive manner

期刊

出版社

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2022.04.066

关键词

Cytochrome C; Metabolism; Ca2+; Channelopathy; Mitochondria

资金

  1. NISER
  2. DBT (Govt. India) [BT-BRB-TF-2-2011 & BT/PR8004/MED/30/988/2013]
  3. Max Plank Institute of Molecular Genetics, Berlin

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The importance of TRPV4 in physiology and disease has been studied. It has been found that TRPV4 interacts with Cytochrome C in a calcium-sensitive manner, and this interaction is affected by different mutations and the presence of different metal ions.
The importance of TRPV4 in physiology and disease has been reported by several groups. Recently we have reported that TRPV4 localizes in the mitochondria in different cellular systems, regulates mito-chondrial metabolism and electron transport chain functions. Here, we show that TRPV4 colocalizes with Cytochrome C (Cyt C), both in resting as well as in activated conditions. Amino acid region 592-630 of TRPV4 (termed as Fr592-630) that also covers TM4-Loop-TM5 region (which is also a hotspot of several pathogenic mutations) interacts with Cyt C, in a Ca2+-sensitive manner. This interaction is also variable and sensitive to other divalent and trivalent cations (i.e., Cu2+, Mn2+, Ni2+, Zn2+, Fe3+). Key residues of TRPV4 involved in these interactions remain conserved throughout the vertebrate evolution. Accord-ingly, this interaction is variable in the case of different pathogenic mutations (R616Q, F617L, L618P, V620I). Our data suggest that the TRPV4-Cyt C complex differs due to different mutations and is sensitive to the presence of different metal ions. We propose that TRPV4-Cyt C complex formation is important for physiological functions and relevant for TRPV4-induced channelopathies. (C) 2022 Elsevier Inc. All rights reserved.

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