Molecular Interactions Of Lymphoid Cell Receptors

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

This project takes advantage of the laboratory's expertise in studying molecular interactions and molecular structure. Specifically, following up on our previous structural studies of the tapasin-like molecule, TAPBPR, we have recently determined the X-ray crystallographic structure of the major chaperone component of the peptide-loading complex (PLC), tapasin, in complex with an MHC-I molecule, HLA-B*44:05. This structure extends our knowledge of the structural details of how MHC-I molecules load with peptides, the molecular conformational adjustments that are made by the chaperone, tapasin, to stabilize a peptide receptive conformation of the MHC-I molecule, and the catalytic role that tapasin plays in allowing peptide exchange favoring high affinity peptides. These fundamental observations refine our molecular understanding the peptide loading process. In addition to these structural studies, we have generated TAPBPR knockout mice and are studying the role of TAPBPR and tapasin in the processes of antigen presentation and cross-presentation. Of particular importance, we have compared our X-ray structural studies of tapasin and TAPBPR with those performed in several other laboratories, noting similarities and differences in the structures we observe as compared to those determined for different MHC-I alleles and by different methods. Putting together our own findings with those reported by others, we understand better the role that molecular flexibility plays in allowing the monomorphic chaperones Tapasin and TAPBPR to interact and catalyze peptide loading across a very wide selection of distinct MHC-I molecules. Recent efforts have explored the contributions of common mutations of Tapasin and TAPBPR found in many cancers. Such mutations results in defects in the antigen presentation pathway and explain how many tumors may escape immune surveillance.