Perera Luke A, Ron David
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom
Cold Spring Harb Perspect Biol. 2023 Mar 1;15(3):a041265. doi: 10.1101/cshperspect.a041265.
The endoplasmic reticulum (ER)-localized Hsp70 chaperone, BiP, undergoes a rapid, reversible and inactivating post-translational modification. This covalent modification complements the slower, conventional unfolded protein response (UPR) in matching the supply of active Hsp70 chaperone to the protein folding demand within the ER lumen. Long believed to be ADP-ribosylation, we now know this modification to be AMPylation (adenylylation) of BiP's threonine 518. Here, we review the discovery of the responsible enzyme (the Fic domain-containing protein FICD), the structural and biochemical basis of the inactivating modification and the discovery of FICD's dual role as the enzyme that both AMPylates and deAMPylates BiP. The structural basis of BiP recognition by FICD and recent in vitro insights into oligomeric state-mediated regulation of FICD's antagonistic enzymatic activities are also reviewed, the latter in the context of how such a regulatory system may arise in cells. Last, we consider the physiological significance of BiP AMPylation and speculate on the fitness benefits of this metazoan-specific adaptation.
内质网（ER）定位的热休克蛋白70（Hsp70）分子伴侣BiP会经历一种快速、可逆且使其失活的翻译后修饰。这种共价修饰在使活性Hsp70分子伴侣的供应与内质网腔中蛋白质折叠需求相匹配方面，补充了较慢的传统未折叠蛋白反应（UPR）。长期以来人们一直认为这种修饰是ADP核糖基化，现在我们知道这种修饰是BiP的苏氨酸518的腺苷酸化（腺苷酰化）。在此，我们综述了负责该修饰的酶（含Fic结构域的蛋白FICD）的发现、失活修饰的结构和生化基础，以及FICD作为对BiP进行腺苷酰化和去腺苷酰化的酶的双重作用的发现。还综述了FICD识别BiP的结构基础以及最近关于寡聚状态介导的FICD拮抗酶活性调节的体外研究见解，后者是在这样一种调节系统如何在细胞中产生的背景下进行的。最后，我们考虑了BiP腺苷酰化的生理意义，并推测了这种后生动物特异性适应的适应性益处。
