The evolutionarily conserved C-terminal peptide of troponin I is an independently configured regulatory structure to function as a myofilament Ca2+-desensitizer

• Published in: Journal of molecular and cellular cardiology Vol. 136; pp. 42 - 52
• Main Authors: Wong, Sienna, Feng, Han-Zhong, Jin, J.-P.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.11.2019
• Subjects: C-terminal end segment; Cardiac muscle; Diastolic function; Myofilament Ca2+-desensitization; Peptide drug; Troponin I; HcTnI-C27; cTnI; pCa50; SUMO; Cardiac muscle; Myofilament Ca2+-desensitization; EDL; HcTnI-C27-H; Tx3; Diastolic function; Troponin I; Peptide drug; C-terminal end segment
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2019.09.002

The C-terminal end segment of troponin subunit I (TnI) is a structure highly conserved among the three muscle type-specific isoforms and across vertebrate species. Partial deletion or point mutation in this segment impairs cardiac muscle relaxation. In the present study, we characterized the C-terminal 27 amino acid peptide of human cardiac TnI (HcTnI-C27) for its role in modulating muscle contractility. Biologically or chemically synthesized HcTnI-C27 peptide retains an epitope structure in physiological solutions similarly to that in intact TnI as recognized by an anti-TnI C-terminus monoclonal antibody (mAb TnI-1). Protein binding studies found that HcTnI-C27 retains the binding affinity for tropomyosin as previously shown with intact cardiac TnI. A restrictive cardiomyopathy mutation R192H in this segment abolishes the bindings to mAb TnI-1 and tropomyosin, demonstrating a pathogenic loss of function. Contractility studies using skinned muscle preparations demonstrated that addition of HcTnI-C27 peptide reduces the Ca2+-sensitivity of myofibrils without decreasing maximum force production. The results indicate that the C-terminal end segment of TnI is a regulatory element of troponin, which retains the native configuration in the form of free peptide to confer an effect on myofilament Ca2+-desensitization. Without negative inotropic impact, this short peptide may be developed into a novel reagent to selectively facilitate cardiac muscle relaxation at the activated state as a potential treatment for heart failure. •The C-terminal end segment of troponin I is a highly conserved structure.•Deletion or point mutation in this segment impairs cardiac muscle relaxation.•TnI C-terminal terminal peptide retains native conformation and binds tropomyosin.•The C27 peptide reduces myofibril Ca2+-sensitivity without decreasing maximum force.•The results demonstrate a potential mechanism for the treatment of heart failure.