Gkogkas Christos, Middleton Susan, Kremer Anna M, Wardrope Caroline, Hannah Matthew, Gillingwater Thomas H, Skehel Paul
The Centre for Neuroscience Research, The University of Edinburgh, The Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
Hum Mol Genet. 2008 Jun 1;17(11):1517-26. doi: 10.1093/hmg/ddn040. Epub 2008 Feb 8.
A mis-sense point mutation in the human VAPB gene is associated with a familial form of motor neuron disease that has been classified as Amyotrophic Lateral Sclerosis type VIII. Affected individuals suffer from a spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) or an atypical slowly progressing form of ALS. Mammals have two homologous VAP genes, vapA and vapB. VAPA and VAPB share 76% similar or identical amino acid residues; both are COOH-terminally anchored membrane proteins enriched on the endoplasmic reticulum. Several functions have been ascribed to VAP proteins including membrane trafficking, cytoskeleton association and membrane docking interactions for cytoplasmic factors. It is shown here that VAPA and VAPB are expressed in tissues throughout the body but at different levels, and that they are present in overlapping but distinct regions of the endoplasmic reticulum. The disease-associated mutation in VAPB, VAPB(P56S), lies within a highly conserved N-terminal region of the protein that shares extensive structural homology with the major sperm protein (MSP) from nematodes. The MSP domain of VAPA and VAPB is found to interact with the ER-localized transcription factor ATF6. Over expression of VAPB or VAPB(P56S) attenuates the activity of ATF6-regulated transcription and the mutant protein VAPB(P56S) appears to be a more potent inhibitor of ATF6 activity. These data indicate that VAP proteins interact directly with components of ER homeostatic and stress signalling systems and may therefore be parts of a previously unidentified regulatory pathway. The mis-function of such regulatory systems may contribute to the pathological mechanisms of degenerative motor neuron disease.
人类VAPB基因中的一个错义点突变与一种家族性运动神经元疾病相关，该疾病已被归类为VIII型肌萎缩侧索硬化症。受影响的个体患有脊髓性肌萎缩症（SMA）、肌萎缩侧索硬化症（ALS）或一种非典型的缓慢进展型ALS。哺乳动物有两个同源的VAP基因，即vapA和vapB。VAPA和VAPB有76%的氨基酸残基相似或相同；两者都是在内质网上富集的COOH末端锚定膜蛋白。VAP蛋白具有多种功能，包括膜运输、细胞骨架结合以及细胞质因子的膜对接相互作用。本文表明，VAPA和VAPB在全身组织中表达，但水平不同，并且它们存在于内质网的重叠但不同的区域。VAPB中的疾病相关突变VAPB(P56S)位于该蛋白高度保守的N末端区域内，该区域与线虫的主要精子蛋白（MSP）具有广泛的结构同源性。发现VAPA和VAPB的MSP结构域与内质网定位的转录因子ATF6相互作用。VAPB或VAPB(P56S)的过表达会减弱ATF6调节的转录活性，并且突变蛋白VAPB(P56S)似乎是ATF6活性的更有效抑制剂。这些数据表明，VAP蛋白直接与内质网稳态和应激信号系统的成分相互作用，因此可能是先前未鉴定的调节途径的一部分。这种调节系统的功能失调可能导致退行性运动神经元疾病的病理机制。
