Disulfide isomerization reactions in titin immunoglobulin?domains enable a mode of protein elasticity.

The response of titin to mechanical forces is a major determinant of the function of the heart. When placed under a pulling force， the unstructured regions of titin uncoil while its immunoglobulin (Ig) domains unfold and extend. Using single-molecule atomic force microscopy， we show that disulfide isomerization reactions within Ig domains enable a third mechanism of titin elasticity. Oxidation of Ig domains leads to non-canonical disulfide bonds that stiffen titin while enabling force-triggered isomerization reactions to more extended states of the domains. Using sequence and structural analyses， we show that 21% of titin's I-band Ig domains contain a conserved cysteine triad that can engage in disulfide isomerization reactions. We propose that imbalance of the redox status of myocytes can have immediate consequences for the mechanical properties of the sarcomere via alterations of the oxidation state of titin domains.