Why the study?
Although CSRP3 mutations are linked to dilated and hypertrophic cardiomyopathy, the exact role of its disordered linker region remains unclear.
Evolutionary and molecular dynamics analyses of the CSRP3 protein reveal that its disordered linker region is highly flexible and varies in length across taxa, which may modulate its function and role in cardiomyopathies.
Linker flexibility and length variation may modulate CSRP3 function; leaves open its regulatory role in cardiomyopathy pending experimental validation.
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.
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Chauhan et al. (2023) studied this question.
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