Abstract:
:In cardiac muscle, troponin (Tn) and tropomyosin inhibit actin and myosin interactions through the steric blocking of myosin binding to F-actin. Ca2+ binding to Tn C modulates this inhibition. Thin filaments become activated upon Ca2+ binding, which enables strong binding of myosin with a concomitant release of ATP hydrolysis products and level arm swinging responsible for force generation. Despite this level of description, the current cross-bridge cycle model does not fully define the structural events that take place within Tn during combinatorial myosin and Ca2+ interventions. Here, we studied conformational changes within Tn bound to F-actin and tropomyosin by fluorescence lifetime imaging combined with Förster resonance energy transfer. Fluorescent dye molecules covalently bound to the Tn C C-lobe and Tn I C-terminal domain report Ca2+- and myosin-induced activation of Tn. Reconstituted thin filaments were deposited on a myosin-coated surface similar to an in vitro motility assay setup without filament sliding involved. Under all the tested conditions, Ca2+ was responsible for the most significant changes in Tn activation. Rigor myosin activated Tn at subsaturated Ca2+ conditions but not to the degree seen in thin filaments with Ca2+. ATP-γ-S did not affect Tn activation significantly; however, blebbistatin induced significant activation at subsaturating Ca2+ levels. The relation between the extent of Tn activation and its conformational flexibility suggests that active/inactive Tn states coexist in different proportions that depend on the combination of effectors. These results satisfy an allosteric activation model of the thin filament as a function of Ca2+ and the myosin catalytic cycle state.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Solís C,Kim GH,Moutsoglou ME,Robinson JMdoi
10.1016/j.bpj.2018.08.033subject
Has Abstractpub_date
2018-11-06 00:00:00pages
1762-1769issue
9eissn
0006-3495issn
1542-0086pii
S0006-3495(18)31010-5journal_volume
115pub_type
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