Key result
CSRP3 L44P mutation significantly disrupts LIM1 domain secondary structure and hydrophobic stability in silico.
Why the study?
Cardiomyopathies involve mutations in CSRP3 protein, but rapid screening methods for mutation effects on LIM domain stability are lacking.
This in-silico screening method provides a rapid way to identify key destabilizing mutations in CSRP3, offering insights into the molecular basis of cardiomyopathies and reducing the need for extensive experimental verification.
May guide CSRP3 variant interpretation in cardiomyopathies; hypothesis-generating and requires functional validation before clinical use.
Cardiomyopathies are a severe and chronic cardiovascular burden worldwide, affecting a large cohort in the general population. Cysteine and glycine-rich protein 3 (CSRP3) is one of key proteins implicated in dominant dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). In this study, we device a rapid in-silico screening protocol that creates a mutational landscape map for all possible allowed and disallowed substitutions in the protein of interest. This map provides the structural and functional insights on the stability of LIM domains of CSRP3. Further, the sequence analysis delineates the eukaryotic CSRP3 protein orthologs which complements the mutational map. Next, we also evaluated the effect of HCM/DCM mutations on these domains. One of highly destabilising mutations - L44P (also disease causing) and a neutral mutation - L44M were further subjected to molecular dynamics (MD) simulations. The results establish that L44P substitution affects the LIM domain structure. The present study provides a useful perspective to our understanding of the role of mutations in the CSRP3 LIM domains and their evolution. Experimentally verifying every reported mutation can become challenging both in time and resources used. This study provides a novel screening method for quick identification of key mutation sites for specific protein structures that can reduce the burden on experimental research.
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Chauhan et al. (2021) studied Cardiomyopathy (Hypertrophic and Dilated). In silico mutagenesis (L44P and L44M) vs. Wild-type CSRP3 was evaluated on Protein stability and structural conformation. In silico comprehensive mutagenesis and molecular dynamics simulations revealed that the L44P mutation in the CSRP3 LIM1 domain significantly disrupts secondary structure and hydrophobic interactions.
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