6NPR

Crystal structure of H-2Dd with C84-C139 disulfide in complex with gp120 derived peptide P18-I10

Summary for 6NPR

• Entry DOI: 10.2210/pdb6npr/pdb
• Descriptor: H-2 class I histocompatibility antigen, D-D alpha chain, Beta-2-microglobulin, ARG-GLY-PRO-GLY-ARG-ALA-PHE-VAL-THR-ILE, ... (4 entities in total)
• Functional Keywords: major histocompatibility complex, antigen presentation, immune system
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 6
• Total formula weight: 90090.59

Authors

Toor, J.,McShan, A.C.,Tripathi, S.M.,Sgourakis, N.G. (deposition date: 2019-01-18, release date: 2020-01-22, Last modification date: 2024-10-23)

Primary citation

McShan, A.C.,Devlin, C.A.,Overall, S.A.,Park, J.,Toor, J.S.,Moschidi, D.,Flores-Solis, D.,Choi, H.,Tripathi, S.,Procko, E.,Sgourakis, N.G.
Molecular determinants of chaperone interactions on MHC-I for folding and antigen repertoire selection.
Proc.Natl.Acad.Sci.USA, 116:25602-25613, 2019

PubMed Abstract: The interplay between a highly polymorphic set of MHC-I alleles and molecular chaperones shapes the repertoire of peptide antigens displayed on the cell surface for T cell surveillance. Here, we demonstrate that the molecular chaperone TAP-binding protein related (TAPBPR) associates with a broad range of partially folded MHC-I species inside the cell. Bimolecular fluorescence complementation and deep mutational scanning reveal that TAPBPR recognition is polarized toward the α domain of the peptide-binding groove, and depends on the formation of a conserved MHC-I disulfide epitope in the α domain. Conversely, thermodynamic measurements of TAPBPR binding for a representative set of properly conformed, peptide-loaded molecules suggest a narrower MHC-I specificity range. Using solution NMR, we find that the extent of dynamics at "hotspot" surfaces confers TAPBPR recognition of a sparsely populated MHC-I state attained through a global conformational change. Consistently, restriction of MHC-I groove plasticity through the introduction of a disulfide bond between the α/α helices abrogates TAPBPR binding, both in solution and on a cellular membrane, while intracellular binding is tolerant of many destabilizing MHC-I substitutions. Our data support parallel TAPBPR functions of 1) chaperoning unstable MHC-I molecules with broad allele-specificity at early stages of their folding process, and 2) editing the peptide cargo of properly conformed MHC-I molecules en route to the surface, which demonstrates a narrower specificity. Our results suggest that TAPBPR exploits localized structural adaptations, both near and distant to the peptide-binding groove, to selectively recognize discrete conformational states sampled by MHC-I alleles, toward editing the repertoire of displayed antigens.

PubMed: 31796585
DOI: 10.1073/pnas.1915562116

Experimental method

X-RAY DIFFRACTION (2.37 Å)