Titin PEVK region (PEVK)

The Titin PEVK region is a specialized, intrinsically disordered domain within the giant protein titin (also known as connectin), located in the I-band of the muscle sarcomere (UniProt Q8WZ42). It is characterized by a high density of proline (P), glutamate (E), valine (V), and lysine (K) residues, which allow it to act as an entropic spring that provides passive tension during muscle elongation (Linke & Hamdani, 2014). This region is a major determinant of myocardial diastolic stiffness and is highly regulated by post-translational modifications, particularly phosphorylation by kinases such as protein kinase G (PKG), protein kinase A (PKA), and protein kinase C (PKC) (Hamdani et al., 2013). In diseases like heart failure with preserved ejection fraction (HFpEF), the PEVK region is often hypophosphorylated, contributing to increased ventricular stiffness and diastolic dysfunction (Borbély et al., 2005). While direct-binding small molecules for the PEVK region are not yet in clinical use, it is a primary downstream target for heart failure therapies that enhance cGMP-PKG signaling, such as neprilysin inhibitors and soluble guanylate cyclase stimulators. Understanding the mechanical properties and regulatory pathways of the PEVK region is essential for developing precision treatments for cardiomyopathies and other muscle-related disorders.

Other names

PEVK domainProline-glutamate-valine-lysine-rich regionTitin spring elementConnectin PEVK region

Modulation of passive myocardial stiffness through the regulation of phosphorylation sites within the PEVK domain by cGMP/PKG and cAMP/PKA signaling pathways.