Kinetics and thermodynamics of beta 2-microglobulin binding to the alpha 3domain 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 peptid e 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 witho ut continued beta 2m association with the MHC complex. Therefore, beta 2m i s both a structural component of the MHC complex and a chaperone-like molec ule for MHC folding. In this study we provide data supporting a model in wh ich the chaperone-like role of beta 2m is dependent on initial binding to o nly one of the two beta 2m interfaces with class 1 heavy chain. beta2-Micro globulin binding to an isolated alpha3 domain of the class I MHC heavy chai n accurately models the biochemistry and thermodynamics of beta 2m-driven r efolding. Our results explain a 1000-fold discrepancy between beta 2m bindi ng and refolding of MHC1. The biochemical study of the individual domains o f complex molecules is an important strategy for understanding their dynami c structure and multiple functions.