CHAP is a newly identified Z-disc protein essential for heart and skeletal muscle function

Abstract

SummaryIn recent years, the perception of Z-disc function has changed from a passive anchor for myofilaments that allows transmission of force, to a dynamic multicomplex structure, capable of sensing and transducing extracellular signals. Here, we describe a new Z-disc protein, which we named CHAP (cytoskeletal heart-enriched actin-associated protein), expressed in differentiating heart and skeletal muscle in vitro and in vivo. Interestingly, in addition to its sarcomeric localization, CHAP was also able to translocate to the nucleus. CHAP was associated with filamentous actin in the cytoplasm and the nucleus when expressed ectopically in vitro, but in rat neonatal cardiomyocytes, CHAP disrupted the subcellular localization of a-actinin, another Z-disc protein. More importantly, knockdown of CHAP in zebrafish resulted in aberrant cardiac and skeletal muscle development and function. These findings suggest that CHAP is a critical component of the sarcomere with an important role in muscle development.

Synaptopodin family of natively unfolded, actin binding proteins: physical properties and potential biological functions

“…That is supported by recent findings that synaptopodin 2 expression precedes α-actinin expression (Linnemann et al 2010). On the other hand, overexpression of CHAP resulted in disorganization of α-actinin (Beqqali et al 2010).…”

“…Although synaptopodin 2 stimulates actin polymerization in solution, it is thought that synaptopodin family members work together with specific isoforms of α-actinin in cells to promote actin polymerization (Asanuma et al 2005;Beqqali et al 2010). HEK cells do not contain appreciable α-actinin 4 or synaptopodin and have no stress fibers.…”

“…Other members of the synaptopodin family were discovered in avian smooth muscle (fesselin or synaptopodin 2) (Leinweber et al 1999) and in heart and skeletal muscle (myopodin, genethonin-2 or synaptopodin 2) (Weins et al 2001). The last member of the synaptopodin family of proteins, the synaptopodin 2-like protein is found in heart and skeletal muscle tissue and is better known under the names tritopodin (Claeys et al 2009) or CHAP (Beqqali et al 2010). These family members are compared in Fig.…”

Atrial fibrillation: the role of common and rare genetic variants

“…39,40 The SNP rs10824026 is located on chromosome 10q22, 5-kb upstream of SYNPO2L. 18 Beqqali et al 41 identified the gene as encoding a cytoskeletal protein, which is highly expressed in the Z-disc of cardiac and skeletal muscle. They renamed it CHAP, cytoskeletal heart-enriched actin-associated protein.…”

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice

“…SYNPO2L and MYOZ1 encode signalling proteins that localise to the Z-disc and modulate cardiac sarcomeric function. 71,72 CAV1 is an important membrane protein, which plays a role in cellular signalling, and has been demonstrated to interact with ion channels, including HCN4 and KCNN3. [73][74][75][76] In addition to the variants identified in the aforementioned GWAS for AF, common variants that have previously been implicated in GWAS for Brugada syndrome have also been demonstrated to influence risk in AF.…”