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TAPBPR employs a ligand-independent docking mechanism to chaperone MR1 molecules
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2022-06-20 , DOI: 10.1038/s41589-022-01049-9
Andrew C McShan 1, 2 , Christine A Devlin 3 , Georgia F Papadaki 1, 2 , Yi Sun 1, 2 , Adam I Green 2 , Giora I Morozov 1, 2 , George M Burslem 2, 4 , Erik Procko 3 , Nikolaos G Sgourakis 1, 2
Affiliation  

Chaperones tapasin and transporter associated with antigen processing (TAP)-binding protein related (TAPBPR) associate with the major histocompatibility complex (MHC)-related protein 1 (MR1) to promote trafficking and cell surface expression. However, the binding mechanism and ligand dependency of MR1/chaperone interactions remain incompletely characterized. Here in vitro, biochemical and computational studies reveal that, unlike MHC-I, TAPBPR recognizes MR1 in a ligand-independent manner owing to the absence of major structural changes in the MR1 α2-1 helix between empty and ligand-loaded molecules. Structural characterization using paramagnetic nuclear magnetic resonance experiments combined with restrained molecular dynamics simulations reveals that TAPBPR engages conserved surfaces on MR1 to induce similar adaptations to those seen in MHC-I/TAPBPR co-crystal structures. Finally, nuclear magnetic resonance relaxation dispersion experiments using 19F-labeled diclofenac show that TAPBPR can affect the exchange kinetics of noncovalent metabolites with the MR1 groove, serving as a catalyst. Our results support a role of chaperones in stabilizing nascent MR1 molecules to enable loading of endogenous or exogenous cargo.



中文翻译:


TAPBPR 采用不依赖配体的对接机制来陪伴 MR1 分子



分子伴侣塔帕蛋白和抗原加工相关转运蛋白 (TAP) 结合蛋白相关 (TAPBPR) 与主要组织相容性复合物 (MHC) 相关蛋白 1 (MR1) 结合,促进运输和细胞表面表达。然而,MR1/伴侣相互作用的结合机制和配体依赖性仍未完全表征。体外生化和计算研究表明,与 MHC-I 不同,TAPBPR 以不依赖配体的方式识别 MR1,因为空分子和配体负载分子之间的 MR1 α 2-1螺旋不存在重大结构变化。使用顺磁核磁共振实验与受限分子动力学模拟相结合的结构表征表明,TAPBPR 与 MR1 上的保守表面接合,诱导与 MHC-I/TAPBPR 共晶结构中看到的类似的适应。最后,使用19 F标记的双氯芬酸进行的核磁共振弛豫分散实验表明,TAPBPR 可以影响非共价代谢物与 MR1 凹槽的交换动力学,充当催化剂。我们的结果支持伴侣在稳定新生 MR1 分子以实现内源性或外源性货物的装载方面的作用。

更新日期:2022-06-21
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