Dataset Information

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

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.

SUBMITTER: Chauhan PK

PROVIDER: S-EPMC10090389 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Chauhan Pankaj Kumar PK Sowdhamini R R

Frontiers in genetics 20230329

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 ...[more]

PMID: 37065494

Similar Datasets

Project description:BackgroundSkeletal muscle mass and strength are crucial determinants of health. Muscle mass loss is associated with weakness, fatigue, and insulin resistance. In fact, it is predicted that controlling muscle atrophy can reduce morbidity and mortality associated with diseases such as cancer cachexia and sarcopenia.MethodsWe analyzed gene expression data from muscle of mice or human patients with diverse muscle pathologies and identified LMCD1 as a gene strongly associated with skeletal muscle function. We transiently expressed or silenced LMCD1 in mouse gastrocnemius muscle or in mouse primary muscle cells and determined muscle/cell size, targeted gene expression, kinase activity with kinase arrays, protein immunoblotting, and protein synthesis levels. To evaluate force, calcium handling, and fatigue, we transduced the flexor digitorum brevis muscle with a LMCD1-expressing adenovirus and measured specific force and sarcoplasmic reticulum Ca2+ release in individual fibers. Finally, to explore the relationship between LMCD1 and calcineurin, we ectopically expressed Lmcd1 in the gastrocnemius muscle and treated those mice with cyclosporine A (calcineurin inhibitor). In addition, we used a luciferase reporter construct containing the myoregulin gene promoter to confirm the role of a LMCD1-calcineurin-myoregulin axis in skeletal muscle mass control and calcium handling.ResultsHere, we identify LIM and cysteine-rich domains 1 (LMCD1) as a positive regulator of muscle mass, that increases muscle protein synthesis and fiber size. LMCD1 expression in vivo was sufficient to increase specific force with lower requirement for calcium handling and to reduce muscle fatigue. Conversely, silencing LMCD1 expression impairs calcium handling and force, and induces muscle fatigue without overt atrophy. The actions of LMCD1 were dependent on calcineurin, as its inhibition using cyclosporine A reverted the observed hypertrophic phenotype. Finally, we determined that LMCD1 represses the expression of myoregulin, a known negative regulator of muscle performance. Interestingly, we observed that skeletal muscle LMCD1 expression is reduced in patients with skeletal muscle disease.ConclusionsOur gain- and loss-of-function studies show that LMCD1 controls protein synthesis, muscle fiber size, specific force, Ca2+ handling, and fatigue resistance. This work uncovers a novel role for LMCD1 in the regulation of skeletal muscle mass and function with potential therapeutic implications.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets