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利用高速原子力显微镜研究工作状态下的单个 CaMKII 全酶。

Imaging single CaMKII holoenzymes at work by high-speed atomic force microscopy.

机构信息

Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.

WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.

出版信息

Sci Adv. 2023 Jun 30;9(26):eadh1069. doi: 10.1126/sciadv.adh1069.

DOI:10.1126/sciadv.adh1069
PMID:37390213
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10313165/
Abstract

Ca/calmodulin-dependent protein kinase II (CaMKII) plays a pivotal role in synaptic plasticity. It is a dodecameric serine/threonine kinase that has been highly conserved across metazoans for over a million years. Despite the extensive knowledge of the mechanisms underlying CaMKII activation, its behavior at the molecular level has remained unobserved. In this study, we used high-speed atomic force microscopy to visualize the activity-dependent structural dynamics of rat/hydra/ CaMKII with nanometer resolution. Our imaging results revealed that the dynamic behavior is dependent on CaM binding and subsequent pT286 phosphorylation. Among the species studies, only rat CaMKIIα with pT286/pT305/pT306 exhibited kinase domain oligomerization. Furthermore, we revealed that the sensitivity of CaMKII to PP2A in the three species differs, with rat, , and hydra being less dephosphorylated in that order. The evolutionarily acquired features of mammalian CaMKIIα-specific structural arrangement and phosphatase tolerance may differentiate neuronal function between mammals and other species.

摘要

钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）在突触可塑性中起着关键作用。它是一种十二聚体丝氨酸/苏氨酸激酶，在超过一百万年的时间里，在后生动物中高度保守。尽管人们对 CaMKII 激活的机制有了广泛的了解，但它在分子水平上的行为仍然没有被观察到。在这项研究中，我们使用高速原子力显微镜以纳米分辨率可视化大鼠/水螅/ CaMKII 的活性依赖性结构动力学。我们的成像结果表明，这种动态行为依赖于 CaM 的结合和随后的 pT286 磷酸化。在研究的物种中，只有带有 pT286/pT305/pT306 的大鼠 CaMKIIα表现出激酶结构域寡聚化。此外，我们揭示了三种物种中 CaMKII 对 PP2A 的敏感性不同，大鼠、 和水螅的去磷酸化程度依次降低。哺乳动物 CaMKIIα 特异性结构排列和磷酸酶耐受性的进化获得的特征可能会区分哺乳动物和其他物种之间的神经元功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/4ca2f5a1e0fe/sciadv.adh1069-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/ad29fa2fe5c9/sciadv.adh1069-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/8e6823c25cf2/sciadv.adh1069-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/9d672ca73ecb/sciadv.adh1069-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/74d893d110f1/sciadv.adh1069-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/6624431533ba/sciadv.adh1069-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/4ca2f5a1e0fe/sciadv.adh1069-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/ad29fa2fe5c9/sciadv.adh1069-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/8e6823c25cf2/sciadv.adh1069-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/9d672ca73ecb/sciadv.adh1069-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/74d893d110f1/sciadv.adh1069-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/6624431533ba/sciadv.adh1069-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f67/10313165/4ca2f5a1e0fe/sciadv.adh1069-f6.jpg

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