2YPK

Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms

Summary for 2YPK

• Entry DOI: 10.2210/pdb2ypk/pdb
• Related: 2YPL
• Descriptor: HLA CLASS I HISTOCOMPATIBILITY ANTIGEN, B-57 ALPHA CHAIN, BETA-2-MICROGLOBULIN, KF11 P24 GAG PEPTIDE, ... (4 entities in total)
• Functional Keywords: immune system, micropolymorphism
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Membrane; Single-pass type I membrane protein: P18465; Secreted: P61769; Capsid protein p24: Virion (By similarity). Integrase: Virion. Matrix protein p17: Virion (By similarity). Matrix protein p17: Virion. Nucleocapsid protein p7: Virion (By similarity). Reverse transcriptase/ribonuclease H: Virion (By similarity): Q70XD7
• Total number of polymer chains: 3
• Total formula weight: 44524.63

Authors

Stewart-Jones, G.B.,Simpson, P.,Van Der Merwe, P.A.,Easterbrook, P.,Mcmichael, A.J.,Rowland-Jones, S.L.,Jones, E.Y.,Gillespie, G.M. (deposition date: 2012-10-30, release date: 2012-11-28, Last modification date: 2024-11-06)

Primary citation

Stewart-Jones, G.B.,Simpson, P.,Anton Van Der Merwe, P.,Easterbrook, P.,Mcmichael, A.J.,Rowland-Jones, S.L.,Jones, E.Y.,Gillespie, G.M.
Structural Features Underlying T-Cell Receptor Sensitivity to Concealed Mhc Class I Micropolymorphisms.
Proc.Natl.Acad.Sci.USA, 109:E3483-, 2012

PubMed Abstract: Polymorphic differences distinguishing MHC class I subtypes often permit the presentation of shared epitopes in conformationally identical formats but can affect T-cell repertoire selection, differentially impacting autoimmune susceptibilities and viral clearance in vivo. The molecular mechanisms underlying this effect are not well understood. We performed structural, thermodynamic, and functional analyses of a conserved T-cell receptor (TCR) which is frequently expanded in response to a HIV-1 epitope when presented by HLA-B*5701 but is not selected by HLA-B*5703, which differs from HLA-B*5701 by two concealed polymorphisms. Our findings illustrate that although both HLA-B*57 subtypes display the epitope in structurally conserved formats, the impact of their polymorphic differences occurs directly as a consequence of TCR ligation, primarily because of peptide adjustments required for TCR binding, which involves the interplay of polymorphic residues and water molecules. These minor differences culminate in subtype-specific differential TCR-binding kinetics and cellular function. Our data demonstrate a potential mechanism whereby the most subtle MHC class I micropolymorphisms can influence TCR use and highlight their implications for disease outcomes.

PubMed: 23161907
DOI: 10.1073/PNAS.1207896109

Experimental method

X-RAY DIFFRACTION (1.95 Å)