Methods for treating cardiac disease by modifying an N-terminal domain of troponin I

A method of screening for a modulator of the N-terminal structure of cardiac troponin I (cTnI) comprising

• (a) incubating a full-length cardiac troponin I in the presence and absence of a candidate modulator;
• (b) assessing the N-terminal structure of the cardiac troponin I;
• and
• (c) identifying a candidate modulator as a modulator of N-terminal structure of cardiac troponin I when the N-terminal structure of cTnI in the absence of said modulator differs from the N-terminal structure of cTnI in the presence of said modulator.

A method of screening for a modulator of cardiac troponin I (cTnI) activity comprising

• (a) incubating a full-length cardiac troponin I in the presence and absence of a candidate modulator;
• (b) assessing cardiac troponin I activity;
• and
• (c) identifying a candidate modulator as a modulator of cardiac troponin I activity when the activity of cTnI in the absence of said candidate modulator differs from the activity of cTnI in the presence of said candidate modulator.

A method of screening for a modulator of cardiac troponin calcium (Ca2+) binding affinity comprising

• (a) incubating a cardiomyocyte preparation comprising a cardiac troponin I comprising a serine residue selected from the group consisting of Ser23 of SEQ ID NO:2 and Ser24 of SEQ ID NO:2 in the presence and absence of a candidate modulator;
• (b) measuring the level of contraction of the preparation;
• and
• (c) identifying a candidate modulator as a modulator of cardiac troponin I when the level of contraction of the preparation in the absence of said modulator differs from the level in the presence of said modulator.

A method of screening for a modulator of cardiac troponin I proteolytic cleavage comprising

• (a) contacting cytoplasmic components of a cardiomyocyte and a cardiac troponin I comprising a serine residue selected from the group consisting of Ser23 of SEQ ID NO:2 and Ser24 of SEQ ID NO:2 in the presence and absence of a candidate modulator;
• (b) measuring the level of N-terminal truncation of said cardiac troponin I;
• and
• (c) identifying a candidate modulator as a modulator of cardiac troponin I proteolytic cleavage when the cleavage level of cTnI in the absence of said modulator differs from the cleavage level of cTnI in the presence of said modulator.