Structure of a Classical MHC Class I Molecule That Binds “Non-Classical” Ligands

Chee Seng Hee,Marcia M Miller,Bernhard Loll,Oliver Daumke,Song Gao,Andreas Ziegler,Barbara Uchanska-Ziegler,Christopher Dascher

doi:10.1371/journal.pbio.1000557

Abstract

Author SummaryProteins encoded by the major histocompatibility complex (MHC) play crucial roles in vertebrate immune systems, presenting pathogen-derived protein fragments to receptors on effector cells. In contrast, some non-classical MHC class I proteins such as CD1 molecules possess a hydrophobic groove that allows them to display lipids. Chicken MHC-Y is a genetic region outside the core MHC that harbors several immune-related genes, among them YF1*7.1, which encodes a protein whose structure we solved in this study. YF1*7.1 is an MHC class I molecule that exhibits the architecture typical of classical MHC class I antigens but possesses a hydrophobic binding groove that binds non-peptidic ligands. By using lipid-binding assays, we show that this molecule can indeed bind lipids. Therefore, YF1*7.1 bridges, at least in structural terms, the traditional gap between classical and non-classical MHC class I molecules. Lipid-binding YF1 proteins might serve the chicken to enlarge its otherwise very small repertoire of antigen-presenting MHC class I molecules. Furthermore, comparative analyses of the two protein subunits of classical MHC molecules revealed a structural feature in chickens that appears to be shared by non-mammalian but not by mammalian vertebrates. This unique feature is indicative of a structure-dependent co-evolution of two genetically unlinked genes in non-mammalian species.

Highlights

The immune systems of birds differ in several important aspects from those of mammals, for example in relying on the bursa of Fabricius, and not on bone marrow, for the production of a diverse B cell repertoire [1], the presence of a major histocompatibility complex (MHC) is a unifying feature [2]
In the chicken (Gallus gallus domesticus), MHC genes are located on the same micro-chromosomal arm in two regions termed MHC-B and MHC-Y that are physically, but not genetically, linked due to a chromosomal segment that supports a high degree of recombination between the two regions [6]
A further distinct structural feature that YF1*7.1 shares with chicken BF2*2101 molecules [15], but not with classical or nonclassical MHC class I molecules from human, rhesus macaque, mouse, rat, cattle, as well as chicken CD1 molecules, is the particular location and conformation of the heavy chain (HC) loop 1 (Loop1) (Figures 2A, 5A)

Summary

Introduction

The immune systems of birds differ in several important aspects from those of mammals, for example in relying on the bursa of Fabricius, and not on bone marrow, for the production of a diverse B cell repertoire [1], the presence of a major histocompatibility complex (MHC) is a unifying feature [2]. The MHC-B region resembles the mammalian MHC, e.g. with regard to its influence on the rapid rejection of transplants [7], but has been termed a ‘‘minimal essential MHC’’ due to its small size [8] It plays a prominent role in genetic resistance, to virally induced tumors [9]. The MHC-Y region, on the other hand, is thought to be associated with a moderate degree of allograft rejection [12] and to influence the fate of tumors induced by Rous Sarcoma virus [13] It contains at least one polymorphic class I locus, YF1, which encodes a class I heavy chain (HC) that associates with b2-microglobulin (b2m) and is ubiquitously transcribed in both adult and embryonic chickens. The YF1*7.1 complex exhibits the typical architecture of

Author Summary

A Structural Peculiarity Characterizes Chicken Classical Class I Molecules

Conclusions

Materials and Methods