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NIMA 相关激酶 9 调节心脏中必需肌球蛋白轻链的磷酸化。

NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart.

机构信息

Kardiogenetikzentrum Heidelberg, University Hospital of Heidelberg, Heidelberg, Germany.

DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Berlin, Germany.

出版信息

Nat Commun. 2022 Oct 20;13(1):6209. doi: 10.1038/s41467-022-33658-2.

DOI:10.1038/s41467-022-33658-2
PMID:36266340
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9585074/
Abstract

To adapt to changing hemodynamic demands, regulatory mechanisms modulate actin-myosin-kinetics by calcium-dependent and -independent mechanisms. We investigate the posttranslational modification of human essential myosin light chain (ELC) and identify NIMA-related kinase 9 (NEK9) to interact with ELC. NEK9 is highly expressed in the heart and the interaction with ELC is calcium-dependent. Silencing of NEK9 results in blunting of calcium-dependent ELC-phosphorylation. CRISPR/Cas9-mediated disruption of NEK9 leads to cardiomyopathy in zebrafish. Binding to ELC is mediated via the protein kinase domain of NEK9. A causal relationship between NEK9 activity and ELC-phosphorylation is demonstrated by genetic sensitizing in-vivo. Finally, we observe significantly upregulated ELC-phosphorylation in dilated cardiomyopathy patients and provide a unique map of human ELC-phosphorylation-sites. In summary, NEK9-mediated ELC-phosphorylation is a calcium-dependent regulatory system mediating cardiac contraction and inotropy.

摘要

为了适应不断变化的血液动力学需求，调节机制通过钙依赖和非依赖机制来调节肌动球蛋白动力学。我们研究了人必需肌球蛋白轻链（ELC）的翻译后修饰，并确定丝氨酸/苏氨酸激酶 NIMA 相关激酶 9（NEK9）与 ELC 相互作用。NEK9 在心脏中高度表达，并且与 ELC 的相互作用是钙依赖性的。沉默 NEK9 导致钙依赖性 ELC 磷酸化减弱。CRISPR/Cas9 介导的 NEK9 缺失会导致斑马鱼出现心肌病。NEK9 通过蛋白激酶结构域与 ELC 结合。体内遗传敏感实验证明了 NEK9 活性与 ELC 磷酸化之间存在因果关系。最后，我们观察到扩张型心肌病患者中 ELC 磷酸化显著上调，并提供了人类 ELC 磷酸化位点的独特图谱。总之，NEK9 介导的 ELC 磷酸化是一种钙依赖性调节系统，介导心脏收缩和变力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/3d860a8e8133/41467_2022_33658_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/52131ae5f341/41467_2022_33658_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/ad30d0adba25/41467_2022_33658_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/783de5de06bd/41467_2022_33658_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/b1fa98f8974f/41467_2022_33658_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/457051b34536/41467_2022_33658_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/4e7f40e73022/41467_2022_33658_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/db7ec9cd41c3/41467_2022_33658_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/3d860a8e8133/41467_2022_33658_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/52131ae5f341/41467_2022_33658_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/ad30d0adba25/41467_2022_33658_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/783de5de06bd/41467_2022_33658_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/b1fa98f8974f/41467_2022_33658_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/457051b34536/41467_2022_33658_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/4e7f40e73022/41467_2022_33658_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/db7ec9cd41c3/41467_2022_33658_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9147/9585074/3d860a8e8133/41467_2022_33658_Fig8_HTML.jpg

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