Abstract
About a fourth of the human proteome is anchored by transmembrane helices (TMHs) to lipid membranes. TMHs require multiple hydrophobic residues for spanning membranes, and this shows a striking resemblance with the requirements for peptide binding to major histocompatibility complex (MHC) class I. It, therefore, comes as no surprise that bioinformatics analysis predicts an over-representation of TMHs among strong MHC class I (MHC-I) binders. Published peptide elution studies confirm that TMHs are indeed presented by MHC-I. This raises the question how membrane proteins are processed for MHC-I (cross-)presentation, with current research focusing on soluble antigens. The presentation of membrane-buried peptides is likely important in health and disease, as TMHs are considerably conserved and their presentation might prevent escape mutations by pathogens. Therefore, it could contribute to the disease correlations described for many human leukocyte antigen haplotypes.
Highlights
Human leukocyte antigen (HLA)-A and HLA-B code for major histocompatibility complex (MHC) class I, which mainly presents peptide fragments derived by proteasomal degradation of “self ” proteins on the cell surface of the antigen presenting cell to cytolytic T cells [1,2,3]
This polymorphism provides an evolutionary advantage, because pathogens cannot develop resistance by mutating residues critical for binding to all HLA haplotypes. We reason that another way how resistance is prevented is by the presentation of stretches of amino acids which are critical for protein function: those located within transmembrane helices (TMHs) of integral membrane proteins
We found a strong correlation (r = 0.88) between these hydrophobic preference scores and the percentages of predicted HLA-binding peptides derived from TMHs (Figure 1D)
Summary
Our present knowledge of antigen presentation is exclusively based on that of soluble antigens, and we currently cannot explain how antigen presenting cells can self- and cross-present integral membrane proteins Both these processes can be expected to require unique, yet unknown, mechanisms and this might well relate to the disease-associations of specific HLA haplotypes. As we explained in this Opinion article, this super type preferentially presents epitopes that are immediately adjacent to transmembrane helices and perhaps medullary thymic epithelial cells cannot efficiently present these peptide fragments This would result in incomplete negative selection and a population of self-reactive cytolytic T cells, which might contribute to the pathology of these inflammatory diseases. Resolving how TMHs are processed for antigen self-presentation and cross-presentation should allow for a better understanding of immunology, and it might allow for new insights into the mechanisms of the disease-associations of HLA haplotypes
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