Titin (PEVK domain) (TTN)

Titin (also known as connectin) is a giant filamentous protein that spans half the sarcomere from the Z-disc to the M-line, serving as a molecular spring and scaffold (UniProt P12847). The PEVK domain, named for its enrichment in proline (P), glutamate (E), valine (V), and lysine (K) residues, is a disordered region within the I-band of titin that contributes significantly to the passive elasticity of cardiac and skeletal muscle (PubMed: 24508242). At physiological sarcomere lengths, the PEVK domain unfolds and extends, generating passive tension that resists stretch and aids in elastic recoil during muscle relaxation (PubMed: 24035140). Mutations or altered splicing of the PEVK domain are linked to various cardiomyopathies, including dilated cardiomyopathy (DCM) and heart failure with preserved ejection fraction (HFpEF), where increased stiffness impairs diastolic filling (PubMed: 24508242). Therapeutic strategies focus on modulating PEVK stiffness through post-translational modifications, such as phosphorylation by protein kinases (e.g., PKA, PKG), or by targeting the splicing factor RBM20 to alter the length of the PEVK segment (PubMed: 22265405). Drugs that increase cGMP levels, such as PDE5 inhibitors or sGC stimulators, promote PKG-mediated phosphorylation of the PEVK domain, thereby reducing myocardial stiffness in heart failure patients (PubMed: 24035140).

Other names

Connectin PEVK regionTTN PEVK domainTitin I-band PEVK segment

Modulation of passive myocardial stiffness through phosphorylation-induced changes in the persistence length of the PEVK domain or through alternative splicing of the PEVK segment.