3D25

Crystal structure of HA-1 minor histocompatibility antigen bound to human class I MHC HLA-A2

3D25 の概要

• エントリーDOI: 10.2210/pdb3d25/pdb
• 分子名称: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Nonameric peptide from HA-1, ... (4 entities in total)
• 機能のキーワード: mhc, hla-a2, secondary anchor residue, glycoprotein, immune system, minor histocompatibility antigen, stem cell transplantation, immune response
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P01892; Secreted: P61769
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 44385.22

構造登録者

Nicholls, S.,Piper, K.P.,Mohammed, F.,Dafforn, T.R.,Tenzer, S.,Salim, M.,Mahendra, P.,Craddock, C.,van Endert, P.,Schild, H.,Cobbold, M.,Engelhard, V.H.,Moss, P.A.H.,Willcox, B.E. (登録日: 2008-05-07, 公開日: 2009-02-10, 最終更新日: 2024-10-09)

主引用文献

Nicholls, S.,Piper, K.P.,Mohammed, F.,Dafforn, T.R.,Tenzer, S.,Salim, M.,Mahendra, P.,Craddock, C.,van Endert, P.,Schild, H.,Cobbold, M.,Engelhard, V.H.,Moss, P.A.,Willcox, B.E.
Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition
Proc.Natl.Acad.Sci.USA, 106:3889-3894, 2009

PubMed Abstract: T cell recognition of minor histocompatibility antigens (mHags) underlies allogeneic immune responses that mediate graft-versus-host disease and the graft-versus-leukemia effect following stem cell transplantation. Many mHags derive from single amino acid polymorphisms in MHC-restricted epitopes, but our understanding of the molecular mechanisms governing mHag immunogenicity and recognition is incomplete. Here we examined antigenic presentation and T-cell recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide dimorphism (HA-1(H) versus HA-1(R)) in the HMHA1 gene. The HA-1(H) peptide is restricted by HLA-A2 and is immunogenic in HA-1(R/R) into HA-1(H) transplants, while HA-1(R) has been suggested to be a "null allele" in terms of T cell reactivity. We found that proteasomal cleavage and TAP transport of the 2 peptides is similar and that both variants can bind to MHC. However, the His>Arg change substantially decreases the stability and affinity of HLA-A2 association, consistent with the reduced immunogenicity of the HA-1(R) variant. To understand these findings, we determined the structure of an HLA-A2-HA-1(H) complex to 1.3A resolution. Whereas His-3 is accommodated comfortably in the D pocket, incorporation of the lengthy Arg-3 is predicted to require local conformational changes. Moreover, a soluble TCR generated from HA-1(H)-specific T-cells bound HA-1(H) peptide with moderate affinity but failed to bind HA-1(R), indicating complete discrimination of HA-1 variants at the level of TCR/MHC interaction. Our results define the molecular mechanisms governing immunogenicity of HA-1, and highlight how single amino acid polymorphisms in mHags can critically affect both MHC association and TCR recognition.

PubMed: 19234124
DOI: 10.1073/pnas.0900411106

実験手法

X-RAY DIFFRACTION (1.3 Å)