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Selective deletion of the NH2-terminal variable region of cardiac troponin T in ischemia reperfusion by myofibril-associated mu-calpain cleavage.

Abstract
The structure of the NH2-terminal region of troponin T (TnT) is hypervariable among the muscle type-specific isoforms and is also regulated by alternative RNA splicing. This region does not contain binding sites for other thin filament proteins, but alteration of its structure affects the Ca2+ regulation of muscle contraction. Here we report a truncated cardiac TnT produced during myocardial ischemia reperfusion. Amino acid sequencing and protein fragment reconstruction determined that it is generated by a posttranslational modification selectively removing the NH2-terminal variable region and preserving the conserved core structure of TnT. Triton X-100 extraction of cardiac muscle fibers promoted production of the NH2-terminal truncated cardiac TnT (cTnT-ND), indicating a myofibril-associated proteolytic activity. Mu-calpain is a myofibril-associated protease and is known to degrade TnT. Supporting a role of mu-calpain in producing cTnT-ND in myocardial ischemia reperfusion, calpain inhibitors decreased the level of cTnT-ND in Triton-extracted myofibrils. Mu-calpain treatment of the cardiac myofibril and troponin complex specifically reproduced cTnT-ND. In contrast, mu-calpain treatment of isolated cardiac TnT resulted in nonspecific degradation, suggesting that this structural modification is relevant to physiological structures of the myofilament. Triton X-100 treatment of transgenic mouse cardiac myofibrils overexpressing fast skeletal muscle TnT produced similar NH2-terminal truncations of the endogenous and exogenous TnT, despite different amino acid sequences at the cleavage site. With the functional consequences of removing the NH2-terminal variable region of TnT, the mu-calpain-mediated proteolytic modification of TnT may act as an acute mechanism to adjust muscle contractility under stress conditions.
AuthorsZhiling Zhang, Brandon J Biesiadecki, Jian-Ping Jin
JournalBiochemistry (Biochemistry) Vol. 45 Issue 38 Pg. 11681-94 (Sep 26 2006) ISSN: 0006-2960 [Print] United States
PMID16981728 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Tropomyosin
  • Troponin I
  • Troponin T
  • Octoxynol
  • Peptide Hydrolases
  • Calpain
  • mu-calpain
Topics
  • Amino Acid Sequence
  • Animals
  • Calpain (antagonists & inhibitors, metabolism)
  • Cattle
  • Chickens
  • In Vitro Techniques
  • Mice
  • Molecular Sequence Data
  • Muscle Fibers, Fast-Twitch (drug effects)
  • Myocardium (metabolism)
  • Myofibrils (enzymology)
  • Octoxynol (pharmacology)
  • Peptide Hydrolases (metabolism)
  • Protein Processing, Post-Translational (drug effects)
  • Rats
  • Reperfusion Injury (chemically induced, metabolism)
  • Sequence Deletion
  • Tropomyosin (metabolism)
  • Troponin I (metabolism)
  • Troponin T (chemistry, genetics)

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