MECHANISM OF PEPTIDE LOADING ONTO HUMAN MHC CLASS II MOLECULES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 该项目的目标是确定多肽负载到人类MHC II类分子上的机制。MHC II类分子与多肽结合非常紧密，半衰期为几天到几周。空的MHC II类分子有聚集的趋势，它们以不变的链聚集在内质网中，像肽一样占据结合槽。在内体多肽装载室中，不变链被一组酶降解，不变链的片段多肽留在凹槽中。去除夹蛋白多肽需要人类白细胞抗原-DM的作用，并使结合槽空缺，无法与微生物多肽结合。我们定义了MHC II类分子与人类白细胞抗原-DM相互作用的分子要求。我们发现，人类白细胞抗原-DM结合需要释放多肽的N-末端部分。基于这一见解，我们现在正试图在结构层面上描述这种相互作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of the project is to determine the mechanisms of peptide loading onto human MHC class II molecules. MHC class II molecules bind peptides very tightly, with half-lives of several days to weeks. Empty MHC class II molecules have a tendency to aggregate and they assemble in the ER with invariant chain, which occupies the binding groove like a peptide. In the endosomal peptide loading compartment, invariant chain is degraded by a set of proteases, leaving the CLIP peptide of invariant chain in the groove. Removal of the CLIP peptide requires the action of HLA-DM and makes the binding groove vacant for binding of microbial peptides. We have defined the molecular requirements for the interaction of MHC class II molecules with HLA-DM. We found that HLA-DM binding required release of the N-terminal part of the peptide. Based on this insight, we are now attempting to characterize this interaction at a structural level.