NDLI: The Cardiac Ca2+-Sensitive Regulatory Switch, a System in Dynamic Equilibrium

Content Provider	PubMed Central
Author	Robinson, John M. Cheung, Herbert C. Dong, Wenji
Abstract	The Ca2+-sensitive regulatory switch of cardiac muscle is a paradigmatic example of protein assemblies that communicate ligand binding through allosteric change. The switch is a dimeric complex of troponin C (TnC), an allosteric sensor for Ca2+, and troponin I (TnI), an allosteric reporter. Time-resolved equilibrium Förster resonance energy transfer (FRET) measurements suggest that the switch activates in two steps: a TnI-independent Ca2+-priming step followed by TnI-dependent opening. To resolve the mechanistic role of TnI in activation we performed stopped-flow FRET measurements of activation after rapid addition of a lacking component (Ca2+ or TnI) and deactivation after rapid chelation of Ca2+. Time-resolved measurements, stopped-flow measurements, and Ca2+-titration measurements were globally analyzed in terms of a new quantitative dynamic model of TnC-TnI allostery. The analysis provided a mesoscopic parameterization of distance changes, free energy changes, and transition rates among the accessible coarse-grained states of the system. The results reveal that 1), the Ca2+-induced priming step, which precedes opening, is the rate-limiting step in activation; 2), closing is the rate-limiting step in de-activation; 3), TnI induces opening; 4), there is an incompletely deactivated population when regulatory Ca2+ is not bound, which generates an accessory pathway of activation; and 5), there is incomplete activation by Ca2+—when regulatory Ca2+ is bound, a 3:2 mixture of dynamically interconverting open (active) and primed-closed (partially active) conformers is observed (15°C). Temperature-dependent stopped-flow FRET experiments provide a near complete thermokinetic parameterization of opening: the enthalpy change (ΔH = −33.4 kJ/mol), entropy change (ΔS = −0.110 kJ/mol/K), heat capacity change (ΔC p = −7.6 kJ/mol/K), the enthalpy of activation (δ ‡ = 10.6 kJ/mol) and the effective barrier crossing attempt frequency (ν adj = 1.8 × 104 s−1).
Related Links	http://dx.doi.org/10.1529/biophysj.108.131318
Ending Page	4789
Page Count	18
Starting Page	4772
File Format	PDF
ISSN	00063495
e-ISSN	15420086
Journal	Biophysical Journal
Issue Number	10
Volume Number	95
Language	English
Publisher	The Biophysical Society
Publisher Date	2008-11-01
Access Restriction	Open
Rights Holder	The Biophysical Society
Subject Keyword	Biophysics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Biophysics

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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