Isoform-specific variation in the intrinsic disorder of troponin I.
Various intrinsic disorder (ID) prediction algorithms were applied to the three tissue isoforms of troponin I (TnI). The results were interpreted in terms of the known structure and dynamics of troponin. In line with previous results, all isoforms of TnI were predicted to have large stretches of ID. The predictions show that the C-termini of all isoforms are extensively disordered as is the N-terminal extension of the cardiac isoform. Cardiac TnI likely belongs to the group of intrinsically disordered signalling hub proteins. For a given portion of the protein sequence, most ID prediction approaches indicate isoform-dependent variations in the probability of disorder. Comparison of machine learning and physically based approaches suggests the ID variations are only partially attributable to local variations in the ratio of charged to hydrophobic residues. The VSL2B algorithm predicts the largest variations in ID across the isoforms, with the cardiac isoform having the highest probability of structured regions, and the fast-skeletal isoform having no intrinsic structure. The region corresponding to residues 57-95 of the fast-skeletal isoform, known to form a coiled coil substructure with troponin T, was highly variable between isoforms. The isoform-specific ID variations may have mechanistic significance, modulating the extent to which conformational fluctuations in tropomyosin are communicated to the troponin complex. We discuss structural mechanisms for this communication. Overall, the results motivate the development of predictors designed to address relative levels of disorder between highly similar proteins.
Hoffman
Ryan M B
RM
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Sykes
Brian D
BD
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D016415:Sequence Alignment; D014335:Tropomyosin / Q000378:metabolism*; D019210:Troponin I / Q000737:chemistry / Q000378:metabolism*
D020033:Protein Isoforms; D014335:Tropomyosin; D019210:Troponin I; D002118:Calcium