Thermodynamic and Kinetic Analysis of a Peptide−Class I MHC Interaction
Highlights the Noncovalent Nature and Conformational Dynamics of the Class I
Heterotrimer†
Posted on 2003-04-11 - 00:00
The class I major histocompatibility (MHC) molecule is a heterotrimer composed of a heavy
chain, the small subunit β2-microglobulin (β2m), and a peptide. Fluorescence anisotropy has been used to
assay the interaction of a labeled peptide with a recombinant, soluble form of the class I MHC HLA-A2.
Consistent with earlier work, peptide binding is shown to be a two-step process limited by a conformational
rearrangement in the heavy chain/β2m heterodimer. However, we identify two pathways for peptide
dissociation from the heterotrimer: (1) initial peptide dissociation leaving a heavy chain/β2m heterodimer
and (2) initial dissociation of β2m, followed by peptide dissociation from the heavy chain. Eyring analyses
of rate constants measured as a function of temperature permit for the first time a complete thermodynamic
characterization of peptide binding. We find that in this case peptide binding is mostly entropically driven,
likely reflecting the hydrophobic character of the peptide binding groove and the peptide anchor residues.
Thermodynamic and kinetic analyses of peptide−MHC interactions as performed here may be of practical
use in the engineering of peptides with desired binding properties and will aid in the interpretation of the
effects of MHC and peptide substitutions on peptide binding and T cell reactivity. Finally, our data suggest
a role for β2m in dampening conformational dynamics in the heavy chain. Remaining conformational
variability in the heavy chain once β2m has bound may be a mechanism to promote promiscuity in peptide
binding.
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Binz, Anne-Kathrin; Rodriguez, Rene C.; Biddison, William E.; Baker, Brian M. (2016). Thermodynamic and Kinetic Analysis of a Peptide−Class I MHC Interaction
Highlights the Noncovalent Nature and Conformational Dynamics of the Class I
Heterotrimer†. ACS Publications. Collection. https://doi.org/10.1021/bi034077m
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