000101648 001__ 101648
000101648 005__ 20230519145459.0
000101648 0247_ $$2doi$$a10.1074/jbc.RA120.016012
000101648 0248_ $$2sideral$$a124274
000101648 037__ $$aART-2021-124274
000101648 041__ $$aeng
000101648 100__ $$aHornos, Felipe
000101648 245__ $$aThe muscle-relaxing C-terminal peptide from troponin I populates a nascent helix, facilitating binding to tropomyosin with a potent therapeutic effect
000101648 260__ $$c2021
000101648 5060_ $$aAccess copy available to the general public$$fUnrestricted
000101648 5203_ $$aThe conserved C-terminal end segment of troponin I (TnI) plays a critical role in regulating muscle relaxation. This function is retained in the isolated C-terminal 27 amino acid peptide (residues 184-210) of human cardiac TnI (HcTnI-C27): When added to skinned muscle fibers, HcTnI-C27 reduces the Ca2+-sensitivity of activated myofibrils and facilitates relaxation without decreasing the maximum force production. However, the underlying mechanism of HcTnI-C27 function is unknown. We studied the conformational preferences of HcTnI-C27 and a myopathic mutant, Arg192His, (HcTnI-C27-H). Both peptides were mainly disordered in aqueous solution with a nascent helix involving residues from Trp191 to Ile195, as shown by NMR analysis and molecular dynamics simulations. The population of nascent helix was smaller in HcTnIC27-H than in HcTnI-C27, as shown by circular dichroism (CD) titrations. Fluorescence and isothermal titration calorimetry (ITC) showed that both peptides bound tropomyosin (aTm), with a detectably higher affinity (~10 µM) of HcTnIC27 than that of HcTnI-C27-H (~15 µM), consistent with an impaired Ca2+-desensitization effect of the mutant peptide on skinned muscle strips. Upon binding to aTm, HcTnI-C27 acquired a weakly stable helix-like conformation involving residues near Trp191, as shown by transferred nuclear Overhauser effect spectroscopy and hydrogen/deuterium exchange experiments. With the potent Ca2+-desensitization effect of HcTnI-C27 on skinned cardiac muscle from a mouse model of hypertrophic cardiomyopathy, the data support that the C-terminal end domain of TnI can function as an isolated peptide with the intrinsic capacity of binding tropomyosin, providing a promising therapeutic approach to selectively improve diastolic function of the heart.
000101648 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000101648 590__ $$a5.485$$b2021
000101648 592__ $$a1.871$$b2021
000101648 594__ $$a8.8$$b2021
000101648 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b94 / 297 = 0.316$$c2021$$dQ2$$eT1
000101648 593__ $$aCell Biology$$c2021$$dQ1
000101648 593__ $$aBiochemistry$$c2021$$dQ1
000101648 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000101648 700__ $$aFeng, Han-Zhong
000101648 700__ $$aRizzuti, Bruno
000101648 700__ $$aPalomino-Schätzlein, Martina
000101648 700__ $$aWieczorek, David
000101648 700__ $$aNeira, José L.
000101648 700__ $$aJin, J.-P.
000101648 773__ $$g296 (2021), 100228 [18 pp.]$$pJ. biol. chem.$$tJournal of Biological Chemistry$$x0021-9258
000101648 8564_ $$s3348195$$uhttps://zaguan.unizar.es/record/101648/files/texto_completo.pdf$$yVersión publicada
000101648 8564_ $$s3374773$$uhttps://zaguan.unizar.es/record/101648/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000101648 909CO $$ooai:zaguan.unizar.es:101648$$particulos$$pdriver
000101648 951__ $$a2023-05-18-14:54:50
000101648 980__ $$aARTICLE