Chaperone-mediated MHC-I peptide exchange in antigen presentation

Abstract

This work focuses on molecules that are encoded by the major histocompatibility complex (MHC) and that bind self-, foreign- or tumor-derived peptides and display these at the cell surface for recognition by receptors on T lymphocytes (T cell receptors, TCR) and natural killer (NK) cells. The past few decades have accumulated a vast knowledge base of the structures of MHC molecules and the complexes of MHC/TCR with specificity for many different peptides. In recent years, the structures of MHC-I molecules complexed with chaperones that assist in peptide loading have been revealed by X-ray crystallography and cryogenic electron microscopy. These structures have been further studied using mutagenesis, molecular dynamics and NMR approaches. This review summarizes the current structures and dynamic principles that govern peptide exchange as these relate to the process of antigen presentation.

Keywords: MHC; MHC-I/TAPBPR; MHC-I/tapasin; PLC; antigen presentation; chaperones; major histocompatibility complex; peptide exchange; structural immunology.

Figure 1

MHC molecules and structures. (a) MHC-I structure and domains (PDB entry 3mre; Reiser et al., 2014 ▸). (b) MHC-II structure and domains (PDB entry 3c5j; Dai et al., 2008 ▸). Illustrations from PDB coordinates and EMD maps were prepared with PyMOL (version 2.5.4, Schrödinger) and ChimeraX (Pettersen et al., 2021 ▸).

Figure 2

Chaperone/MHC and antigen presentation pathways. (a) MHC-I/tapasin classical antigen presentation pathway. (b) MHC-II/DM classical antigen presentation pathway (Blum et al., 2013 ▸). (c) MHC-I/TAPBPR auxiliary antigen presentation pathway.

Figure 3

Strategies for obtaining the chaperone-mediated MHC-I complex. (a) Surface plasmon resonance (SPR) experiments: B44/6-mer binds better (K _D = 0.34 µM) than (b) that of B44/9-mer (K _D = 1.31 µM), which indicates that MHC-I with the short/truncated peptide binds tighter to tapasin. (c) No electron density is observed in the peptide groove of HLA-B44:05 in the complex with tapasin (PDB entry 7tue). The electron density of the 2(F _o − mF _c) map is shown in blue, contoured at 1σ.

Figure 4

Overall structures of MHC-I with the chaperones. (a) Structure of TAPBPR/H2-D^d (PDB entry 5wer; Jiang et al., 2017 ▸). (b) Structure of TAPBPR/H2-D^b (PDB entry 5opi; Thomas & Tampé, 2017 ▸). (c) Structure of tapasin/HLA-B44 (PDB entry 7tue; Jiang et al., 2022 ▸). (d) Structure of tapasin/H2-D^b/ERp57 (PDB entry 7qng; Müller et al., 2022 ▸) where ERp57 has been omitted for clarity.

Figure 5

Peptide groove comformational changes and three major interaction sites. (a) TAPBPR/H2-D^d (PDB entry 5wer, blue and firebrick) is superimposed with H2-D^d-5-mer (PDB entry 5wes, gray). Three major interaction sites are numbered. (b) Tapasin/HLA-B44 (PDB entry 7tue, marine blue and magenta) is superimposed with HLA-B44-6-mer (PDB entry 7tud, gray). Tapasin draws the α2–1 helix of HLA-B44 closer by about 3.0 Å and results in the groove being open. The three major interaction sites are numbered, and shown in detail in (c).

Figure 6

Tapasin/MHC-I domain movements and PLC. (a) Tapasin/B44:05, B44-6-mer and tapasin (PDB entry 3f8u) superimposed on the upper domains. Surface representation for the domains of α3, β₂m and IgC are observed moving about 9.1, 9.8 and 16.3 Å, respectively. (b) Model of PLC, cryoEM map resolution at 3.7 A (PDB entry 7qpd; EMD-14119; Domnick et al., 2022 ▸).

Figure 7

Flexibility of dynamic loops. (a) Tapasin loop E11–K20 modeled from various complexes is superimposed on the α1 helix. MHC-I is blue and the tapasin of each complex is color-coded according to the legend in the panel [PDB entries 3f8u (6), 7tue (4) and 6eny (3) are missing a number of residues on the loop]. The conformation of the loop varies indicating the mobility and flexibility of this loop. The α2–1 helices are drawn towards tapasin in various degrees indicating the openness of peptide groove in different structures. (b) Tapasin loop Q189–H195, the complexes are superimposed on α2–1. The loop interacts with β7 and β8 underneath the peptide-binding groove. Inset: tapasin loop from PDB entries 7tuf and 3f8u, the loop occupies a higher position. When tapasin is complexed with MHC-I (e.g. PDB entries 7qng, 7qpd, 7tue and 6eny), the loop is pushed down by 5–10 Å. (c) Tapasin loop P69–S110 (color) and TAPBPR loop C101–Q126 (gray). Tapasin has a much longer loop P69–S110 (40 aa) than that of TAPBPR (26 aa) which increased the interaction between the β8 loop and S82–K84 of tapasin.

Figure 8

Domain movements of the chaperone tapasin. Tapasin from each complex is superimposed on the top domains (N and IgV domain, residues 2–280) of the AlphaFold2 predicted model (green) as a reference point. The measured distance is between the L293 Cα atoms in the IgC domain, as shown by the number in the figure. The AlphaFold2 model is similar to PDB entry 3f8u.

Figure 9

Structural mechanism of peptide exchange and illustration. (a) Structural mechanism of peptide exchange indicating dynamic intermediate states. State 1 indicates β₂m binding to the heavy chain of MHC-I. State 2 shows the early loading of low-affinity peptides. State 3 displays the initial interaction of tapasin binding to MHC-I. State 4 summarizes the release of the lower-affinity peptide and formation of a peptide receptive complex. State 5 illustrates the binding of a high-affinity peptide, releasing MHC-I from the PLC. (b) The Finger–Palm–Heel model: a mechanical principle [This figure is modified from one previously published by Jiang et al. (2022 ▸) distributed under a Creative Commons CC BY 4.0 licence (https://creativecommons.org/licenses/by/4.0/)].