Kinetics and thermodynamics of beta 2-microglobulin binding to the alpha 3 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 (beta2m). beta2m has been previously shown to play an important role in the folding of the MHC heavy chain without continued beta2m association with the MHC complex. Therefore, beta2m 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 beta2m is dependent on initial binding to only one of the two beta2m 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 beta2m-driven refolding. Our results explain a 1000-fold discrepancy between beta2m 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.
Hebert
A M
AM
Division of Monoclonal Ab, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Strohmaier
J
J
Whitman
M C
MC
Chen
T
T
Gubina
E
E
Hill
D M
DM
Lewis
M S
MS
Kozlowski
S
S
D000818:Animals; D002460:Cell Line; D019277:Entropy; D005822:Genetic Vectors; D006183:H-2 Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006207:Half-Life; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D007700:Kinetics; D051379:Mice; D011485:Protein Binding / Q000235:genetics; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics; D020349:Surface Plasmon Resonance; D013696:Temperature; D013816:Thermodynamics; D014162:Transfection; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D001613:beta 2-Microglobulin