Myofilament Calcium Sensitivity: Mechanistic Insight into TnI Ser-23/24 and Ser-150 Phosphorylation Integration.
Myofilament Calcium Sensitivity: Mechanistic Insight into TnI Ser-23/24 and Ser-150 Phosphorylation Integration.
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DOI：
10.3389/fphys.2016.00567
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发表时间：
2016
影响因子：
4
通讯作者：
Biesiadecki BJ
中科院分区：
文献类型：
--
作者：
Salhi HE;Hassel NC;Siddiqui JK;Brundage EA;Ziolo MT;Janssen PM;Davis JP;Biesiadecki BJ
肌钙蛋白I（TnI）是心肌收缩和舒张的主要调节因子。在生理和病理应激过程中，TnI通过不同的信号通路在多个残基上差异磷酸化，以使心脏功能与需求相匹配。这些TnI磷酸化的组合可以表现出预期的或意外的功能整合，由此两种磷酸化的功能不同于从单独的每个单独磷酸化的组合功能预测的功能。我们已经表明，TnI Ser-23/24和Ser-150磷酸化表现出功能整合，并同时增加心脏应激反应。在本研究中，我们研究了TnI Ser-23/24和Ser-150的功能整合，以改变心脏收缩。我们假设Ser-23/24和Ser-150磷酸化各自利用不同的分子机制来改变细丝内的TnI结合亲和力。数学模型预测，Ser-23/24和Ser-150磷酸化影响不同的肌钙蛋白I的亲和力内的细丝，明显改变肌钙蛋白的Ca 2+结合特性。蛋白质结合实验证实了这一论断，证明假磷酸化的Ser-150降低了分离的TnI对肌动蛋白的亲和力，而Ser-23/24假磷酸化与未磷酸化没有区别。因此，我们的数据支持TnI Ser-23/24影响TnI-TnC结合，而Ser-150磷酸化改变TnI-肌动蛋白结合。通过测量肌钙蛋白交换的皮肤肌细胞中的力发展，我们证明了力的Ca 2+敏感性与TnI上存在的磷酸盐的量直接相关。此外，我们证明，Ser-150假磷酸化钝化Ser-23/24介导的降低钙敏感力的发展，无论是在相同或不同的TnI分子。因此，肌钙蛋白I磷酸化可沿肌丝沿着整合肌钙蛋白。这些数据表明，肌钙蛋白丝氨酸-23/24和丝氨酸-150磷酸化调节肌肉收缩部分通过调节不同的肌钙蛋白相互作用的细丝，它是这些差异机制的组合，提供了了解他们的功能整合。
Troponin I (TnI) is a major regulator of cardiac muscle contraction and relaxation. During physiological and pathological stress, TnI is differentially phosphorylated at multiple residues through different signaling pathways to match cardiac function to demand. The combination of these TnI phosphorylations can exhibit an expected or unexpected functional integration, whereby the function of two phosphorylations are different than that predicted from the combined function of each individual phosphorylation alone. We have shown that TnI Ser-23/24 and Ser-150 phosphorylation exhibit functional integration and are simultaneously increased in response to cardiac stress. In the current study, we investigated the functional integration of TnI Ser-23/24 and Ser-150 to alter cardiac contraction. We hypothesized that Ser-23/24 and Ser-150 phosphorylation each utilize distinct molecular mechanisms to alter the TnI binding affinity within the thin filament. Mathematical modeling predicts that Ser-23/24 and Ser-150 phosphorylation affect different TnI affinities within the thin filament to distinctly alter the Ca2+-binding properties of troponin. Protein binding experiments validate this assertion by demonstrating pseudo-phosphorylated Ser-150 decreases the affinity of isolated TnI for actin, whereas Ser-23/24 pseudo-phosphorylation is not different from unphosphorylated. Thus, our data supports that TnI Ser-23/24 affects TnI-TnC binding, while Ser-150 phosphorylation alters TnI-actin binding. By measuring force development in troponin-exchanged skinned myocytes, we demonstrate that the Ca2+ sensitivity of force is directly related to the amount of phosphate present on TnI. Furthermore, we demonstrate that Ser-150 pseudo-phosphorylation blunts Ser-23/24-mediated decreased Ca2+-sensitive force development whether on the same or different TnI molecule. Therefore, TnI phosphorylations can integrate across troponins along the myofilament. These data demonstrate that TnI Ser-23/24 and Ser-150 phosphorylation regulates muscle contraction in part by modulating different TnI interactions in the thin filament and it is the combination of these differential mechanisms that provides understanding of their functional integration.
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影响因子：
6.1
作者：
Chen S;Zhu P;Guo HM;Solis RS;Wang Y;Ma Y;Wang J;Gao J;Chen JM;Ge Y;Zhuang J;Li J
通讯作者：
Li J
影响因子：
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作者：
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通讯作者：
Wolska, Beata M.
影响因子：
3.5
作者：
Abbott, MB;Dvoretsky, A;Rosevear, PR
通讯作者：
Rosevear, PR
影响因子：
20.1
作者：
Herron, TJ;Korte, FS;McDonald, KS
通讯作者：
McDonald, KS
影响因子：
4.8
作者：
Barbato, JC;Huang, QQ;Jin, JP
通讯作者：
Jin, JP