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Structure of the Human MHC-I Peptide-Loading Complex

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Structure of the Human MHC-I Peptide-Loading Complex LETTER doi:10.1038/nature24627 Structure of the human MHC-I peptide-loading complex Andreas Blees1*, Dovile Januliene2*, Tommy Hofmann3, Nicole Koller1, Carla Schmidt3, Simon Trowitzsch1, Arne Moeller2 & Robert Tampé1 The peptide-loading complex (PLC) is a transient, multisubunit to the cell surface for T-cell recognition3. The PLC can serve a large pool membrane complex in the endoplasmic reticulum that is essential of MHC-I allomorphs and, therefore, fulfills a central function in the for establishing a hierarchical immune response. The PLC differentiation and priming of T lymphocytes and in controlling viral coordinates peptide translocation into the endoplasmic reticulum infections and tumour development. The compositional heterogeneity with loading and editing of major histocompatibility complex class I and the intrinsic dynamic nature of this ER-resident membrane (MHC-I) molecules. After final proofreading in the PLC, stable complex have hindered detailed structural studies. The overall archi- peptide–MHC-I complexes are released to the cell surface to evoke tecture and the structural elements of the PLC that underlie assembly, a T-cell response against infected or malignant cells1,2. Sampling proofreading, and release of peptide–MHC-I complexes are largely of different MHC-I allomorphs requires the precise coordination unknown. of seven different subunits in a single macromolecular assembly, We isolated endogenous PLC from human Burkitt’s lymphoma including the transporter associated with antigen processing cells using the herpes viral inhibitor ICP47 fused to streptavidin- (TAP1 and TAP2, jointly referred to as TAP), the oxidoreductase binding peptide, ICP47–SBP, as bait (Fig. 1a–c). The affinity tag did ERp57, the MHC-I heterodimer, and the chaperones tapasin and not affect the inhibiting function of ICP47, as shown by a single-cell- calreticulin3,4. The molecular organization of and mechanistic based antigen translocation assay (Extended Data Fig. 1a–d). ICP47 events that take place in the PLC are unknown owing to the stabilizes TAP and arrests the PLC in a peptide-depleted state7, thus heterogeneous composition and intrinsically dynamic nature of the blocking the loading and release of MHC-I molecules. Incubation of complex. Here, we isolate human PLC from Burkitt’s lymphoma cell membranes with ICP47–SBP, followed by detergent solubilization cells using an engineered viral inhibitor as bait and determine and affinity purification, resulted in monodisperse PLC containing all the structure of native PLC by electron cryo-microscopy. Two subunits (Fig. 1b, c, Extended Data Fig. 1e and Extended Data Table 2), endoplasmic reticulum-resident editing modules composed of which was further subjected to GraFix8 (Extended Data Fig. 2). In tapasin, calreticulin, ERp57, and MHC-I are centred around TAP in addition to the three polymorphic MHC-I alleles (HLA-A, HLA-B a pseudo-symmetric orientation. A multivalent chaperone network and HLA-C), the non-classical alleles HLA-E, HLA-F, and HLA-G are within and across the editing modules establishes the proofreading incorporated into native PLC (Extended Data Fig. 1e and Extended function at two lateral binding platforms for MHC-I molecules. Data Table 2). Furthermore, we observed two tapasin isoforms (48 and The lectin-like domain of calreticulin senses the MHC-I glycan, 53 kDa) associated with the PLC, both of which were singly N-core whereas the P domain reaches over the MHC-I peptide-binding glycosylated (Fig. 1b and Extended Data Fig. 1e, f). pocket towards ERp57. This arrangement allows tapasin to facilitate We determined the structure of the fully assembled human endo- peptide editing by clamping MHC-I. The translocation pathway of genous PLC by single-particle electron cryo-microscopy (cryo-EM) TAP opens out into a large endoplasmic reticulum lumenal cavity, (Fig. 1d, e, Extended Data Fig. 3 and Extended Data Table 1). The confined by the membrane entry points of tapasin and MHC-I. Two macro molecular complex measures 150 Å by 150 Å and has a total height lateral windows channel the antigenic peptides to MHC-I. Structures of 240 Å across the ER membrane. The anisotropy of the consensus of PLC captured at distinct assembly states provide mechanistic structure emphasizes the dynamic nature of the entire co mplex and insight into the recruitment and release of MHC-I. Our work defines limits the attainable resolution (Fig. 1d). The ER-lumenal domains, the molecular symbiosis of an ABC transporter and an endoplasmic arranged in two editing modules, are well-resolved; however, weaker reticulum chaperone network in MHC-I assembly and provides densities are observed for TAP. The translocation unit displays a high insight into the onset of the adaptive immune response. degree of flexibility and the TAP complex is rotated by approximately Nascent MHC-I heavy chains are chaperoned by the calnexin– 30° around the pseudo-C2 symmetry axis (Fig. 1d, e). Classification calreticulin system in the endoplasmic reticulum (ER). Together into multiple models did not improve the density of TAP or the with β 2-microglobulin (β 2m), MHC-I heavy chains assemble into overall resolution, but revealed distinct structural classes of the PLC heterodimers that act as receptors for antigenic peptides2. Empty (Extended Data Fig. 4). We therefore performed a focused classifica- MHC-I heterodimers are recruited by calreticulin and become part tion and alignment. In the case of TAP, the resolution could not be of the transient macromolecular PLC5,6, where the chaperone tapasin increased. However, the structure of the editing modules was signif- further stabilizes MHC-I molecules. As a disulfide-linked conjugate icantly improved to 7.2 Å (Fig. 2a and Extended Data Fig. 3). Each of with the thiol oxidoreductase ERp57, tapasin is crucial for maintaining the two fully assembled editing modules comprises tapasin, ERp57, the structural stability of the PLC and for facilitating optimal peptide calreticulin, and the MHC-I heterodimer9–12 (Fig. 2a, c, d). Our struc- loading2. After final quality control, in which MHC-I heterodimers ture defines the molecular organization of the ER chaperone network undergo peptide editing, stable peptide–MHC-I complexes are released acting on MHC-I clients. A focused classification on a single editing 1Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Strasse 9, 60438 Frankfurt/Main, Germany. 2Department of Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue Strasse 3, 60438 Frankfurt/Main, Germany. 3Interdisciplinary Research Center HALOmen, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Strasse 3, 06120 Halle/Saale, Germany. *These authors contributed equally to this work. 23 NOVEMBER 2017 | VOL 551 | NATURE | 525 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. RESEARCH LETTER a b c a b Editing module ER lumen 200 1,236 Calreticu li n m 1,048 660 481kDa 146kDa 66kDa kDa ERp57 PLC TAP1TAP2ERp57CalreticulinTapasinMHC-I hcβ 2 130- 150 MHC-I hc 720 PLC 95- 480 75- Tapasin 242 β2m 100 55- 146 90° 45- 66 34- kDa 26- 50 Cytosol 17- * Absorbance at 280 nm TAP1TAP2 10- kDa 0 1 2 3 4 5 ER membrane ER membrane d 150 Å Elution volume (ml) cd 90° 240 Å 180° 90° Low High Resolution e 30° 30° Tapasin ERp57 ER membrane Calreticulin Editing module I 40 Å 60 Å 90° 180° Figure 2 | Overall structural organization of the PLC editing modules. β2m MHC-I hc a, Cryo-EM density of the two pseudo-symmetric editing modules at 7.2 Å, 30° 90° shown in side and top views. b, Side view of the single editing module resolved at 5.8 Å. c, d, Ribbon diagram of the two editing modules in top (c) Translocation Editing module II unit and side (d) views. Tapasin is tilted towards the ER membrane, giving Micelle TAP rise to two lateral windows between the individual editing modules. The entrance points of the single transmembrane helices of tapasin (orange) Figure 1 | Composition and architecture of the human PLC. a, Schematic and MHC-I heavy chains (blue) are indicated. All subunits are coloured as overview of the individual components of the PLC showing TAP1, TAP2, in Fig. 1. Symmetry axes are indicated (dashed line). tapasin, MHC-I heavy chain (hc), β2 m, calreticulin, and ERp57. b , Endogenous human PLC was affinity purified by ICP47–SBP. The presence of all subunits was verified by SDS–PAGE (Coomassie; immunoglobulin-like domain of the cis tapasin, potentially adding to asterisk, ICP47–SBP) followed by immunoblotting. c, Size-exclusion the stability of the PLC (Fig. 2c, d). Cross-linking mass spectrometry chromatography and blue-native PAGE of purified PLC reveals an apparent (XL-MS) confirmed this unexpected crossover arrangement of the molecular mass of approximately 650 kDa. d, The heat map of the PLC two tapasin–ERp57 modules (Fig. 2a, c, d, Extended Data Fig. 7 and consensus model, filtered to its local resolution (Relion), highlights the Extended Data Tables 2, 3), corroborating the importance of ERp57 for intrinsic dynamic nature of the macromolecular assembly. e, The general stabilizing the PLC, besides its crucial role for MHC-I recruitment13–16. architecture of the fully assembled PLC is displayed as a composite map, Our density map exhibits peptide-deficient MHC-I molecules, which where the threshold for each component was adjusted individually to allow are held in place by two major contact sites on tapasin (Fig. 3). The first visualization of all subunits (Extended Data Fig. 5). The pseudo-symmetry binding site is established by residues in the loop between β -strands axis is indicated (dashed lines). Data shown in b and c are representative of at least eight independent experiments. 17 and 18 of the C-terminal immunoglobulin-like domain of tapasin, which latch onto the CD8 recognition loop of the α 3-domain of the MHC-I heavy chains (Fig. 3e). Notably, loop residues S336, H335, and module further improved the map resolution to 5.8 Å and guided H334 of tapasin are positioned close to the conserved MHC-I heavy model building (Fig.
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