Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA.
Bioessays. 2018 Jun;40(6):e1700219. doi: 10.1002/bies.201700219. Epub 2018 Apr 25.
We propose protein localization dependent signal activation (PLDSA) as a model to describe pre-existing protein partitioning between the cytosol, and membrane surface, as a means to modulate signal activation, specificity, and robustness. We apply PLDSA to explain possible molecular links between type II diabetes mellitus (T2DM) and Alzheimer's disease (AD) by describing Ca -mediated interactions between the Src non-receptor tyrosine kinase and p52Shc adaptor protein. We suggest that these interactions may serve as a contributing factor to disease development and progression. In particular, we propose that signaling response is regulated, in part, by Ca -mediated partitioning of lipid-bound and soluble forms of Src and p52shc. Thus, protein-protein interactions that drive signaling in response to extracellular ligand binding are also mediated by partitioning of signaling proteins between membrane-bound and soluble populations. We propose that PLDSA effects may explain, in part, the evolutionary basis of promiscuous protein interaction domains and their importance in cellular function.
我们提出蛋白质定位相关信号激活（PLDSA）作为一种模型来描述细胞质和膜表面之间预先存在的蛋白质分配，作为调节信号激活、特异性和稳健性的一种手段。我们应用 PLDSA 来解释 2 型糖尿病（T2DM）和阿尔茨海默病（AD）之间可能的分子联系，描述 Src 非受体酪氨酸激酶和 p52Shc 衔接蛋白之间 Ca 介导的相互作用。我们认为这些相互作用可能是疾病发展和进展的一个促成因素。特别是，我们提出信号响应受到 Ca 介导的 Src 和 p52shc 的脂结合和可溶性形式的分配的调节。因此，驱动对细胞外配体结合的信号响应的蛋白质-蛋白质相互作用也受到信号蛋白在膜结合和可溶性群体之间分配的介导。我们提出 PLDSA 效应可能部分解释了混杂蛋白相互作用域的进化基础及其在细胞功能中的重要性。
