Bakthisaran Raman, Akula Kranthi Kiran, Tangirala Ramakrishna, Rao Ch Mohan
CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
Biochim Biophys Acta. 2016 Jan;1860(1 Pt B):167-82. doi: 10.1016/j.bbagen.2015.09.017. Epub 2015 Sep 28.
αB-crystallin, once thought to be a lenticular protein, is ubiquitous and has critical roles in several cellular processes that are modulated by phosphorylation. Serine residues 19, 45 and 59 of αB-crystallin undergo phosphorylation. Phosphorylation of S45 is mediated by p44/42 MAP kinase, whereas S59 phosphorylation is mediated by MAPKAP kinase-2. Pathway involved in S19 phosphorylation is not known.
The review highlights the role of phosphorylation in (i) oligomeric structure, stability and chaperone activity, (ii) cellular processes such as apoptosis, myogenic differentiation, cell cycle regulation and angiogenesis, and (iii) aging, stress, cardiomyopathy-causing αB-crystallin mutants, and in other diseases.
Depending on the context and extent of phosphorylation, αB-crystallin seems to confer beneficial or deleterious effects. Phosphorylation alters structure, stability, size distribution and dynamics of the oligomeric assembly, thus modulating chaperone activity and various cellular processes. Phosphorylated αB-crystallin has a tendency to partition to the cytoskeleton and hence to the insoluble fraction. Low levels of phosphorylation appear to be protective, while hyperphosphorylation has negative implications. Mutations in αB-crystallin, such as R120G, Q151X and 464delCT, associated with inherited myofibrillar myopathy lead to hyperphosphorylation and intracellular inclusions. An ongoing study in our laboratory with phosphorylation-mimicking mutants indicates that phosphorylation of R120GαB-crystallin increases its propensity to aggregate.
Phosphorylation of αB-crystallin has dual role that manifests either beneficial or deleterious consequences depending on the extent of phosphorylation and interaction with cytoskeleton. Considering that disease-causing mutants of αB-crystallin are hyperphosphorylated, moderation of phosphorylation may be a useful strategy in disease management. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.
αB-晶状体蛋白曾被认为是一种晶状体蛋白，它广泛存在，并在多种受磷酸化调节的细胞过程中发挥关键作用。αB-晶状体蛋白的丝氨酸残基19、45和59会发生磷酸化。S45的磷酸化由p44/42丝裂原活化蛋白激酶介导，而S59的磷酸化由丝裂原活化蛋白激酶相关激酶-2介导。S19磷酸化所涉及的信号通路尚不清楚。
本综述重点阐述了磷酸化在以下方面的作用：（i）寡聚体结构、稳定性及伴侣活性；（ii）细胞过程，如细胞凋亡、肌源性分化、细胞周期调控及血管生成；（iii）衰老、应激、导致心肌病的αB-晶状体蛋白突变体以及其他疾病。
取决于磷酸化的背景和程度，αB-晶状体蛋白似乎会产生有益或有害的影响。磷酸化会改变寡聚体组装的结构、稳定性、大小分布和动力学，从而调节伴侣活性及各种细胞过程。磷酸化的αB-晶状体蛋白倾向于分配到细胞骨架，进而进入不溶性部分。低水平的磷酸化似乎具有保护作用，而过度磷酸化则有负面影响。与遗传性肌原纤维肌病相关的αB-晶状体蛋白突变，如R120G、Q151X和464delCT，会导致过度磷酸化和细胞内包涵体形成。我们实验室正在进行的一项关于磷酸化模拟突变体的研究表明，R120GαB-晶状体蛋白的磷酸化会增加其聚集倾向。
αB-晶状体蛋白的磷酸化具有双重作用，根据磷酸化程度以及与细胞骨架的相互作用，会产生有益或有害的后果。鉴于导致疾病的αB-晶状体蛋白突变体是过度磷酸化的，调节磷酸化水平可能是疾病管理中的一种有用策略。本文是名为“健康与疾病中的晶状体蛋白生物化学”的特刊的一部分。
