Structure of cardiac muscle troponin C unexpectedly reveals a closed regulatory domain.
The regulation of cardiac muscle contraction must differ from that of skeletal muscles to effect different physiological and contractile properties. Cardiac troponin C (TnC), the key regulator of cardiac muscle contraction, possesses different functional and Ca2+-binding properties compared with skeletal TnC and features a Ca2+-binding site I, which is naturally inactive. The structure of cardiac TnC in the Ca2+-saturated state has been determined by nuclear magnetic resonance spectroscopy. The regulatory domain exists in a "closed" conformation even in the Ca2+-bound (the "on") state, in contrast to all predicted models and differing significantly from the calcium-induced structure observed in skeletal TnC. This structure in the Ca2+-bound state, and its subsequent interaction with troponin I (TnI), are crucial in determining the specific regulatory mechanism for cardiac muscle contraction. Further, it will allow for an understanding of the action of calcium-sensitizing drugs, which bind to cardiac TnC and are known to enhance the ability of cardiac TnC to activate cardiac muscle contraction.
Sia
S K
SK
Department of Biochemistry, Medical Research Council Group in Protein Structure and Function, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Li
M X
MX
Spyracopoulos
L
L
Gagné
S M
SM
Liu
W
W
Putkey
J A
JA
Sykes
B D
BD
D000409:Alanine; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002645:Chickens; D003001:Cloning, Molecular; D004926:Escherichia coli; D008958:Models, Molecular; D008961:Models, Structural; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism*; D017354:Point Mutation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D019209:Troponin C / Q000737:chemistry* / Q000378:metabolism*; D014633:Valine
D011994:Recombinant Proteins; D019209:Troponin C; D014633:Valine; D000409:Alanine; D002118:Calcium