Effects of Cardiac Troponin I Mutation P83S on Contractile Properties and the Modulation by PKA-Mediated Phosphorylation

详细信息    查看全文

• 作者：Yuanhua Cheng ; Steffen Lindert ; Lucas Oxenford ; An-yue Tu ; Andrew D. McCulloch ; Michael Regnier
• 刊名：Journal of Physical Chemistry B
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：120
• 期：33
• 页码：8238-8253
• 全文大小：925K
• 年卷期：0
• ISSN：1520-5207

文摘

cTnI^P82S (cTnI^P83S in rodents) resides at the I-T arm of cardiac troponin I (cTnI) and was initially identified as a disease-causing mutation of hypertrophic cardiomyopathy (HCM). However, later studies suggested this may not be true. We recently reported that introduction of an HCM-associated mutation in either inhibitory-peptide (cTnI^R146G) or cardiac-specific N-terminus (cTnI^R21C) of cTnI blunts the PKA-mediated modulation on myofibril activation/relaxation kinetics by prohibiting formation of intrasubunit contacts between these regions. Here, we tested whether this also occurs for cTnI^P83S. cTnI^P83S increased both Ca²⁺ binding affinity to cTn (K_Ca) and affinity of cTnC for cTnI (K_C–I), and eliminated the reduction of K_Ca and K_C–I observed for phosphorylated-cTnI^WT. In isolated myofibrils, cTnI^P83S maintained maximal tension (T_MAX) and Ca²⁺ sensitivity of tension (pCa₅₀). For cTnI^WT myofibrils, PKA-mediated phosphorylation decreased pCa₅₀ and sped up the slow-phase relaxation (especially for those Ca²⁺ conditions that heart performs in vivo). Those effects were blunted for cTnI^P83S myofibrils. Molecular-dynamics simulations suggested cTnI^P83S moderately inhibited an intrasubunit interaction formation between inhibitory-peptide and N-terminus, but this “blunting” effect was weaker than that with cTnI^R146G or cTnI^R21C. In summary, cTnI^P83S has similar effects as other HCM-associated cTnI mutations on troponin and myofibril function even though it is in the I-T arm of cTnI.