Abstract
Class I Major Histocompatibility Complex (MHC) binds short antigenic peptides with the help of Peptide Loading Complex (PLC), and presents them to T-cell Receptors (TCRs) of cytotoxic T-cells and Killer-cell Immunglobulin-like Receptors (KIRs) of Natural Killer (NK) cells. With more than 10000 alleles, human MHC (Human Leukocyte Antigen, HLA) is the most polymorphic protein in humans. This allelic diversity provides a wide coverage of peptide sequence space, yet does not affect the three-dimensional structure of the complex. Moreover, TCRs mostly interact with HLA in a common diagonal binding mode, and KIR-HLA interaction is allele-dependent. With the aim of establishing a framework for understanding the relationships between polymorphism (sequence), structure (conserved fold) and function (protein interactions) of the human MHC, we performed here a local frustration analysis on pMHC homology models covering 1436 HLA I alleles. An analysis of local frustration profiles indicated that (1) variations in MHC fold are unlikely due to minimally-frustrated and relatively conserved residues within the HLA peptide-binding groove, (2) high frustration patches on HLA helices are either involved in or near interaction sites of MHC with the TCR, KIR, or tapasin of the PLC, and (3) peptide ligands mainly stabilize the F-pocket of HLA binding groove.
Highlights
The sequence-structure-function paradigm plays a central role in structural biology: the primary structure of a protein dictates the three-dimensional structure, which in turn influences the function [1,2,3]
Biophysical basis of Major Histocompatibility Complex (MHC) I polymorphism residue, and the respective level of polymorphism observed within a sequence-structure-function context
We show the existence of local frustration-based energetic footprints of polymorphism, providing a biophysical basis for the previously observed differences between molecular stabilities/cell surface expression levels of different allele groups and T-cell Receptors (TCRs)/Killer-cell Immunglobulin-like Receptors (KIRs)/Peptide Loading Complex (PLC) interactions
Summary
The sequence-structure-function paradigm plays a central role in structural biology: the primary structure (i.e. amino acid sequence) of a protein dictates the three-dimensional structure (fold), which in turn influences the function [1,2,3]. Homology modeling was used to classify a high number of HLA alleles into distinct groups based on peptide interaction patterns [42], binding pocket similarities [43] and surface electrostatics [44]. Biophysical basis of MHC I polymorphism residue (e.g. whether they are important for folding or binding), and the respective level of polymorphism observed within a sequence-structure-function context.
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