Kinetics and thermodynamics of β2-microglobulin binding to the α3 domain of major histocompatibility complex class I heavy chain

The major histocompatibility complex (MHC) class I molecule plays a crucial role in cytotoxic lymphocyte function. Functional class I MHC exists as a heterotrimer consisting of the MHC class I heavy chain, an antigenic peptide fragment, and beta2-microglobulin (beta 2m). beta 2m has been previously shown to play an important role in the folding of the MHC heavy chain without continued beta 2m association with the MHC complex. Therefore, beta 2m is both a structural component of the MHC complex and a chaperone-like molecule for MHC folding. In this study we provide data supporting a model in which the chaperone-like role of beta 2m is dependent on initial binding to only one of the two beta 2m interfaces with class 1 heavy chain. beta2-Microglobulin binding to an isolated alpha3 domain of the class I MHC heavy chain accurately models the biochemistry and thermodynamics of beta 2m-driven refolding. Our results explain a 1000-fold discrepancy between beta 2m binding and refolding of MHC1. The biochemical study of the individual domains of complex molecules is an important strategy for understanding their dynamic structure and multiple functions.