SUMOylation of cardiac myosin binding protein-C reduces its phosphorylation and results in impaired relaxation following treatment with isoprenaline

IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biochemistry & Cell Biology Pub Date : 2024-09-24 DOI:10.1016/j.biocel.2024.106668
Alice Main, Sheon Mary, Yuan Yan Sin, Tom A. Wright, Jiayue Ling, Connor M. Blair, Godfrey L. Smith, Will Fuller, George S. Baillie
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Abstract

Systolic and diastolic functions are coordinated in the heart by myofilament proteins that influence force of contraction and calcium sensitivity. Fine control of these processes is afforded by a variety of post-translation modifications that occur on specific proteins at different times during each heartbeat. Cardiac myosin binding protein-C is a sarcomeric accessory protein whose function is to interact transiently with actin, tropomyosin and myosin. Previously many different types of post-translational modification have been shown to influence the action of myosin binding protein-C and we present the first report that the protein can be modified covalently by the small ubiquitin like modifier protein tag. Analysis by mass spectrometry suggests that there are multiple modification sites on myosin binding protein-C for this tag and single point mutations did not serve to abolish the covalent addition of the small ubiquitin like modifier protein. Functionally, our data from both model human embryonic kidney cells and transfected neonatal cardiac myocytes suggests that the modification reduces phosphorylation of the filament protein on serine 282. In cardiac myocytes, the hypo-phosphorylation coincided with a significantly slower relaxation response following isoprenaline induced contraction. We hypothesise that this novel modification of myosin binding protein-C represents a new level of control that acts to alter the relaxation kinetics of cardiac myocytes.
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心肌肌球蛋白结合蛋白-C 的 SUMOylation 可降低其磷酸化程度,并导致异丙肾上腺素治疗后的松弛功能受损
心脏的收缩和舒张功能是由影响收缩力和钙敏感性的肌丝蛋白协调的。在每次心跳的不同时间,特定蛋白质会发生各种翻译后修饰,从而对这些过程进行精细控制。心肌肌球蛋白结合蛋白-C 是一种肌纤维附属蛋白,其功能是与肌动蛋白、肌钙蛋白和肌球蛋白发生瞬时相互作用。以前曾有多种不同类型的翻译后修饰被证明会影响肌球蛋白结合蛋白-C 的作用,我们首次报道了该蛋白可通过类似泛素修饰蛋白的小标签进行共价修饰。质谱分析表明,肌球蛋白结合蛋白-C上有多个修饰位点,单点突变并不能取消小泛素修饰蛋白的共价添加。从功能上看,我们从人类胚胎肾脏模型细胞和转染的新生心肌细胞中获得的数据表明,这种修饰减少了丝蛋白在丝氨酸 282 上的磷酸化。在心肌细胞中,低磷酸化与异丙肾上腺素诱导收缩后明显减慢的松弛反应相吻合。我们推测,肌球蛋白结合蛋白-C 的这种新型修饰代表了一种新的控制水平,其作用是改变心肌细胞的松弛动力学。
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来源期刊
CiteScore
8.10
自引率
0.00%
发文量
124
审稿时长
19 days
期刊介绍: IJBCB publishes original research articles, invited reviews and in-focus articles in all areas of cell and molecular biology and biomedical research. Topics of interest include, but are not limited to: -Mechanistic studies of cells, cell organelles, sub-cellular molecular pathways and metabolism -Novel insights into disease pathogenesis -Nanotechnology with implication to biological and medical processes -Genomics and bioinformatics
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