Characterization of the human sigma-1 receptor chaperone domain structure and binding immunoglobulin protein (BiP) interactions.
Characterization of the human sigma-1 receptor chaperone domain structure and binding immunoglobulin protein (BiP) interactions.
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人类Sigma-1受体伴侣结构结构和结合免疫球蛋白蛋白（BIP）相互作用的表征。
DOI：
10.1074/jbc.m113.450379
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发表时间：
2013-07-19
期刊：
影响因子：
--
通讯作者：
Schnell JR
中科院分区：
文献类型：
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作者：
Ortega-Roldan JL;Ossa F;Schnell JR
背景：Sigma-1受体是一种受配体调控的膜蛋白伴侣，参与Bip调节和内质网应激反应。结果：人Sigma-1受体的伴侣结构域多为螺旋结构，延伸区较短。结论：Sigma-1受体伴侣结构域涉及配体和胆固醇结合的区域可以被映射到单独的螺旋上。意义：提出了一个描述sigma-1受体Bip和配体相互作用的结构框架。Sigma-1受体(S1R)是一种受配体调控的膜蛋白伴侣，参与内质网应激反应。S1R活性与中枢神经系统疾病有关，包括健忘症、精神分裂症、抑郁症、阿尔茨海默病和成瘾。S1R已被证明通过C-末端结构域调节HSP70结合免疫球蛋白(BiP)和三磷酸肌醇受体钙通道。我们已经开发了细菌表达和将人S1R的伴侣结构域重组到洗涤剂胶束中的方法，使其能够通过溶液核磁共振光谱进行研究。伴侣结构域被发现在N端包含一个螺旋，随后是一个主要的动态区域和一个结构化的螺旋C-末端区域，该区域包含一个包含四个螺旋的膜相关结构域。∼第198-206位残基的螺旋区域具有很强的两亲性，建议将伴侣结构域锚定在胶束和膜上。C-末端区域的三个螺旋与先前发现的胆固醇和药物识别位点密切对应。此外，研究还表明，伴侣结构域与全长Bip或Bip分离的核苷酸结合域相互作用，但不与底物结合域相互作用，表明核苷酸结合域足以与S1R相互作用。
Background: Sigma-1 receptor is a ligand-regulated membrane protein chaperone involved in BiP regulation and the ER stress response. Results: The chaperone domain of human sigma-1 receptor is mostly helical with short extended regions. Conclusion: Regions of the sigma-1 receptor chaperone domain implicated in ligand and cholesterol binding can be mapped to separate helices. Significance: A structural framework for delineating sigma-1 receptor BiP and ligand interactions is presented. The sigma-1 receptor (S1R) is a ligand-regulated membrane protein chaperone involved in the ER stress response. S1R activity is implicated in diseases of the central nervous system including amnesia, schizophrenia, depression, Alzheimer disease, and addiction. S1R has been shown previously to regulate the Hsp70 binding immunoglobulin protein (BiP) and the inositol triphosphate receptor calcium channel through a C-terminal domain. We have developed methods for bacterial expression and reconstitution of the chaperone domain of human S1R into detergent micelles that enable its study by solution NMR spectroscopy. The chaperone domain is found to contain a helix at the N terminus followed by a largely dynamic region and a structured, helical C-terminal region that encompasses a membrane associated domain containing four helices. The helical region at residues ∼198–206 is strongly amphipathic and proposed to anchor the chaperone domain to micelles and membranes. Three of the helices in the C-terminal region closely correspond to previously identified cholesterol and drug recognition sites. In addition, it is shown that the chaperone domain interacts with full-length BiP or the isolated nucleotide binding domain of BiP, but not the substrate binding domain, suggesting that the nucleotide binding domain is sufficient for S1R interactions.