北大医学研究生课程分子免疫学MHCPPT课件.ppt

A model of peptide transport begins with TAP in an inward/cytosol-facing conformation with the NBDs (nucleotide-binding domains) open. A peptide binds a cytosol-facing cavity formed by the TMDs (transmembrane domains), causing a conformational change that is transmitted to the NBDs. This conformational change permits ATP-dependent NBD closure, perhaps by facilitating exchange of ADP on TAP2 for ATP. As the NBDs close, the peptide-binding cavity closes to the cytosol and opens to the ER lumen, creating the closed, outward-facing conformation of TAP. Peptide affinity is markedly reduced in this conformation, and the peptide is hence released into the ER. ATP hydrolysis in the consensus ATPase site is sufficient to destabilize the closed NBDs (hydrolysis may also occur in the degenerate ATPase site, but this is not essential), which re-open to generate the resting conformation. Current Opinion in Immunology 2009, 21:84–91 TAP1和TAP2（抗原处理相关的转运蛋白，transporter associated with antigen processing） 属于膜转运蛋白质，含有6-10个疏水性穿膜区，形成异源双聚体，可将抗原多肽从胞浆转运至内质网 部分肿瘤细胞TAP1表达下降，TAP1基因导入治疗小细胞肺癌 TAP1和TAP2基因突变可引起MHC I类分子缺陷，患者常患呼吸道细菌性感染而不是病毒感染 LMP2和LMP7（low molecular weight protein） 蛋白酶体（Proteasome）的主要活性成分，可水解抗原分子，使其成为小分子多肽。 钙连接蛋白（Calnexin） 分子伴侣，在内质网与MHC I类分子结合，形成稳定复合物 ?外源性抗原被内吞，在内体（Endosome）和溶酶体被变性、水解成多肽。 ?MHC II类分子合成后与Ii分子形成3聚体，在内质体和溶酶体内被蛋白酶水解形成MHC II和CLIP复合物。 ?HLA-DM催化CLIP从MHC解离，促进MHC II类分子与抗原多肽形成复合物。 ?转运至细胞膜。 MHC class II compartment, M II C（MHC II类小室）：一种富含MHC II类分子的溶酶体样细胞器 Schematic representation of MIICs. In professional APCs, both multivesicular (MVB) and multilamellar (MLB) MIICs have been described. The open/empty conformation of HLA-DR (red) has only been observed in the MLB type. HLA-DM (green) is expressed in both compartments, albeit particularly abundant in MLB. The carboxy and amino terminals of invariant chains are still evident in MVBs whereas are mostly processed in MLBs. Electrondense bodies (EDBs) are lysosomal-like MIICs, and have been observed in human monocytes and i