Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex.

分子伴侣TAPBPR和Tapasin与I类主要组织相容性复合物（MHC-1）结合，以促进肽货物的优化（编辑）。在这里，我们使用溶液核磁共振来研究肽交换的机制。我们在保守的MHC-I分子表面上鉴定出TAPBPR诱导的构象变化，这与我们独立确定的复合物X射线结构一致。TAPBPR使空MHC-1中存在的动力学稳定，并随着肽占用的增加而逐渐减弱。根据最终的pMHC-1产品的整体稳定性识别进入的肽，并以天然样构象进行退火，由TAPBPR编辑。我们的结果表明，MHC-1肽的占有率与TAPBPR结合亲和力之间存在反比关系，其中瞬时结合的肽的寿命和结构特征控制位于TAPBPR结合位点附近的构象开关的调节，这触发了TAPBPR的释放。这些结果表明，在肽加载复合物中，塔帕森蛋白具有类似的功能。