Hameroff Stuart R, Craddock Travis J A, Tuszynski J A
Department of Anesthesiology, Center for Consciousness Studies, The University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA.
J Integr Neurosci. 2010 Sep;9(3):253-67. doi: 10.1142/s0219635210002482.
Learning, memory and long-term potentiation (LTP) are supported by factors including post-synaptic calcium ion flux activating and transforming the hexagonal calcium-calmodulin kinase II (CaMKII) holoenzyme. Upon calcium-induced activation, up to six kinase domains extend upward, and up to six kinase domains extend downward from the CaMKII association domain, the fully activated holoenzyme resembling a robotic insect 20 nanometers in length. Each extended kinase domain can be phosphorylated, and able to phosphorylate other proteins, thus potentially further encoding synaptic information at intraneuronal molecular sites for memory storage, processing and distribution. Candidate sites for phosphorylation-encoded molecular memory include microtubules, cylindrical lattice polymers of the protein tubulin. Using molecular modeling, we find spatial dimensions and geometry of the six extended CaMKII kinase domains can precisely match those of microtubule hexagonal lattice neighborhoods (both A- and B-lattices), and show two feasible phosphorylation mechanisms. In one, phosphorylation sites (e.g., valine 208) on a CaMKII extended kinase domain interact with serine 444 on a C-terminal "tail" of tubulin. In the second, the CaMKII kinase domain unfurls, enabling phosphorylation sites to contact threonine and serine sites on the tubulin surface. We suggest sets of six CaMKII kinase domains phosphorylate hexagonal microtubule lattice neighborhoods collectively, e.g., conveying synaptic information as ordered arrays of six "bits", and thus a "byte", with (minimally) 2⁶ (64) possible bit states per CaMKII-microtubule interaction. We model two levels of interaction between CaMKII and microtubules, suggesting a testable framework for molecular memory encoding.
学习、记忆和长时程增强（LTP）受到多种因素的支持，这些因素包括突触后钙离子通量激活并转化六聚体钙调蛋白激酶II（CaMKII）全酶。在钙诱导激活后，多达六个激酶结构域向上延伸，多达六个激酶结构域从CaMKII结合结构域向下延伸，完全激活的全酶类似于一只长20纳米的机器昆虫。每个延伸的激酶结构域都可以被磷酸化，并能够磷酸化其他蛋白质，从而有可能在神经元内部分子位点进一步编码用于记忆存储、处理和分布的突触信息。磷酸化编码分子记忆的候选位点包括微管，它是由微管蛋白组成的圆柱形晶格聚合物。通过分子建模，我们发现六个延伸的CaMKII激酶结构域的空间尺寸和几何形状可以精确匹配微管六边形晶格邻域（A晶格和B晶格）的尺寸和几何形状，并展示了两种可行的磷酸化机制。一种机制是，CaMKII延伸激酶结构域上的磷酸化位点（如缬氨酸208）与微管蛋白C末端“尾巴”上的丝氨酸444相互作用。第二种机制是，CaMKII激酶结构域展开，使磷酸化位点能够接触微管蛋白表面的苏氨酸和丝氨酸位点。我们认为，六个CaMKII激酶结构域的集合共同磷酸化六边形微管晶格邻域，例如，将突触信息作为六个“比特”的有序阵列进行传递，从而形成一个“字节”，每次CaMKII与微管相互作用时（最少）有2⁶（64）种可能的比特状态。我们对CaMKII与微管之间的两级相互作用进行了建模，提出了一个可测试的分子记忆编码框架。
