Computational analysis of the flexibility in the disordered linker region connecting LIM domains in cysteine-glycine-rich protein

Front Genet. 2023 Mar 29:14:1134509. doi: 10.3389/fgene.2023.1134509. eCollection 2023.

Abstract

One of the key proteins that are present in the Z-disc of cardiac tissues, CSRP3, has been implicated in dilated and hypertrophic cardiomyopathy leading to heart failure. Although multiple cardiomyopathy-related mutations have been reported to reside on the two LIM domains and the disordered regions connecting the domains in this protein, the exact role of the disordered linker region is not clear. The linker harbors a few post-translational modification sites and is expected to be a regulatory site. We have carried out evolutionary studies on 5614 homologs spanning across taxa. We also performed molecular dynamics simulations of full-length CSRP3 to show that the length variations and conformational flexibility of the disordered linker could provide additional levels of functional modulation. Finally, we show that the CSRP3 homologs with widely different lengths of the linker regions could display diversity in their functional specifications. The present study provides a useful perspective to our understanding of the evolution of the disordered region between CSRP3 LIM domains.

Keywords: CSRP3; PPI; cardiomyopathy; disordered region; molecular dynamics.

Grants and funding

RS acknowledges funding and support provided by the JC Bose Fellowship (JBR/2021/000006) from the Science and Engineering Research Board, India, and the Bioinformatics Center Grant funded by the Department of Biotechnology, India (BT/PR40187/BTIS/137/9/2021). RS would also like to thank Institute of Bioinformatics and Applied Biotechnology for the funding through her Mazumdar-Shaw Chair in Computational Biology (IBAB/MSCB/182/2022).