Selector function of MHC I molecules is determined by protein plasticity.

Alistair Bailey,Jörn M Werner,Andrew Phillips,Neil Dalchau,Tim Elliott,Rachel Carter,Stephen Emmott

doi:10.1038/srep14928

Alistair Bailey, Jörn M Werner + Show 5 more

Open Access

https://doi.org/10.1038/srep14928

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Abstract

The selection of peptides for presentation at the surface of most nucleated cells by major histocompatibility complex class I molecules (MHC I) is crucial to the immune response in vertebrates. However, the mechanisms of the rapid selection of high affinity peptides by MHC I from amongst thousands of mostly low affinity peptides are not well understood. We developed computational systems models encoding distinct mechanistic hypotheses for two molecules, HLA-B*44:02 (B*4402) and HLA-B*44:05 (B*4405), which differ by a single residue yet lie at opposite ends of the spectrum in their intrinsic ability to select high affinity peptides. We used in vivo biochemical data to infer that a conformational intermediate of MHC I is significant for peptide selection. We used molecular dynamics simulations to show that peptide selector function correlates with protein plasticity, and confirmed this experimentally by altering the plasticity of MHC I with a single point mutation, which altered in vivo selector function in a predictable way. Finally, we investigated the mechanisms by which the co-factor tapasin influences MHC I plasticity. We propose that tapasin modulates MHC I plasticity by dynamically coupling the peptide binding region and α3 domain of MHC I allosterically, resulting in enhanced peptide selector function.

Highlights

Peptides bound to Major histocompatibility complex class I (MHC I) molecules are displayed at the surface of most nucleated cells in jawed vertebrates for surveillance by cytotoxic T-lymphocytes (CTL)[1,2,3]
To quantify peptide selector function in vivo, we measured the fraction of a pulse-labelled cohort of MHC I molecules that were stable at 50 °C, 37 °C and 4 °C as they progressed through the secretory pathway over 120 minutes (Fig. 2A,B, quantified in F,G)
Since the thermal stability of MHC I has been shown to act as a surrogate for the affinity of peptide bound to MHC I10, this allows the quantification of the selection of high affinity peptides by MHC I

Summary

Introduction

Peptides bound to Major histocompatibility complex class I (MHC I) molecules are displayed at the surface of most nucleated cells in jawed vertebrates for surveillance by cytotoxic T-lymphocytes (CTL)[1,2,3]. In tapasin-deficient cells, B*4402 is poor at sampling the peptidome and as a consequence is degraded in the endoplasmic reticulum (ER), while B*4405 is able to effectively select high affinity peptides and present them at the cell surface These observations of allelic differences in intrinsic MHC I peptide selector function imply that tapasin normalizes the peptide selector function of MHC I alleles. Different methods have provided indirect evidence that peptide binding to MHC I is associated with a conformational intermediate[17,18,19,20,21], including molecular dynamics simulations[22,23,24,25] These studies have helped to resolve the apparent paradox of how MHC I molecules of such degenerate specificity can bind peptides with such high affinity, they do not provide a framework for understanding the mechanism of peptide selection inside cells

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