Molecular Biology Consortium, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
SBA School of Science and Engineering, LUMS, Lahore, Pakistan.
Sci Rep. 2022 May 19;12(1):8499. doi: 10.1038/s41598-022-12090-y.
The calcium calmodulin (Ca/CaM) dependent protein kinase II (CaMKII) decodes Ca frequency oscillations. The CaMKIIα isoform is predominantly expressed in the brain and has a central role in learning. I matched residue and organismal evolution with collective motions deduced from the atomic structure of the human CaMKIIα holoenzyme to learn how its ring architecture abets function. Protein dynamic simulations showed its peripheral kinase domains (KDs) are conformationally coupled via lateral spread along the central hub. The underlying β-sheet motions in the hub or association domain (AD) were deconvolved into dynamic couplings based on mutual information. They mapped onto a coevolved residue network to partition the AD into two distinct sectors. A second, energetically stressed sector was added to ancient bacterial enzyme dimers for assembly of the ringed hub. The continued evolution of the holoenzyme after AD-KD fusion targeted the sector's ring contacts coupled to the KD. Among isoforms, the α isoform emerged last and, it alone, mutated rapidly after the poikilotherm-homeotherm jump to match the evolution of memory. The correlation between dynamics and evolution of the CaMKII AD argues single residue substitutions fine-tune hub conformational spread. The fine-tuning could increase CaMKIIα Ca frequency response range for complex learning functions.
钙调蛋白（Ca/CaM）依赖性蛋白激酶 II（CaMKII）解码 Ca 频率振荡。CaMKIIα 同工型主要在大脑中表达，在学习中具有核心作用。我将残基和生物进化与从人 CaMKIIα 全酶的原子结构推断出的集体运动进行匹配，以了解其环结构如何促进功能。蛋白质动态模拟表明，其外围激酶结构域（KDs）通过沿中央枢纽的侧向扩展而在构象上耦联。枢纽或关联域（AD）中的基础β-折叠运动基于互信息被分解为动态耦合。它们映射到共进化残基网络上，将 AD 分成两个不同的扇区。第二个能量紧张的扇区被添加到古老的细菌酶二聚体中，用于组装环形枢纽。AD-KD 融合后全酶的持续进化针对与 KD 耦合的扇区的环接触。在同工型中，α 同工型最后出现，并且仅在变温动物-恒温动物跳跃后迅速突变，以适应记忆的进化。CaMKII AD 的动力学和进化之间的相关性表明，单个残基取代可以微调枢纽构象扩展。这种微调可以增加 CaMKIIα 的 Ca 频率响应范围，以实现复杂的学习功能。
