PDBsum entry 3d25

Immune system

PDB id: 3d25

Contents

Protein chains

274 a.a. *

98 a.a. *

Ligands

VAL-LEU-HIS-ASP-ASP-LEU-LEU-GLU-ALA

Waters ×354

* Residue conservation analysis

PDB id:

3d25

Name:

Immune system

Title:

Crystal structure of ha-1 minor histocompatibility antigen bound to human class i mhc hla-a2

Structure:

Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a. Synonym: mhc class i antigen a 2. Engineered: yes. Beta-2-microglobulin. Chain: b. Fragment: unp residues 22-119. Synonym: beta-2-microglobulin form pi 5.3. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-a, hlaa. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: b2m, cdabp0092, hdcma22p. Synthetic: yes. Other_details: the peptide is commercially synthesized. It is found

Resolution:

1.30Å R-factor: 0.169 R-free: 0.204

Authors:

S.Nicholls,K.P.Piper,F.Mohammed,T.R.Dafforn,S.Tenzer,M.Salim, P.Mahendra,C.Craddock,P.Van Endert,H.Schild,M.Cobbold,V.H.Engelhard, P.A.H.Moss,B.E.Willcox

Key ref:

S.Nicholls et al. (2009). Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition. Proc Natl Acad Sci U S A, 106, 3889-3894. PubMed id: 19234124 DOI: 10.1073/pnas.0900411106

Date:

07-May-08 Release date: 10-Feb-09

Protein chain

P04439  (1A03_HUMAN) -  HLA class I histocompatibility antigen, A alpha chain from Homo sapiens

Seq: 365 a.a.

Struc: 274 a.a.*

Protein chain

P61769  (B2MG_HUMAN) -  Beta-2-microglobulin from Homo sapiens

Seq: 119 a.a.

Struc: 98 a.a.

* PDB and UniProt seqs differ at 19 residue positions (black crosses)

DOI no: 10.1073/pnas.0900411106

Proc Natl Acad Sci U S A 106:3889-3894 (2009)

PubMed id: 19234124

Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition.

S.Nicholls, K.P.Piper, F.Mohammed, T.R.Dafforn, S.Tenzer, M.Salim, P.Mahendra, C.Craddock, P.van Endert, H.Schild, M.Cobbold, V.H.Engelhard, P.A.Moss, B.E.Willcox.

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.

Selected figure(s)

Figure 3.
Crystallographic structure of HLA-A2-VLH at 1.3Å. (A) Overall structure of HLA-A2-VLH complex, with heavy chain (gray), β2m (cyan), and VLH peptide (blue) shown. (B) 2Fo-Fc electron density for the VLH peptide, with primary anchors and P3 to P5 highlighted. (C) Structure of the VLH mHag in the HLA-A2-antigen binding groove, with antigen-binding pockets A to F indicated, and VLH peptide surface indicated in green. The structure highlights relatively poor contacts with pockets E and F. (D) Orientation of H3 in and around the D pocket. H3 packs snugly against the walls of the D pocket, maintaining van der Waal's contacts with Tyr-159, Leu-156, and Gln-155, and also to Asp-4 of the peptide. It is also participates in a hydrogen-bonding network to Gln-155, and peptide residues Asp-4 and Asp-5, via ordered water molecules. Semitransparent peptide surface shown in green.

Figure 4.
Surface plasmon resonance analysis of TCR/HLA-A2-HA-1 interaction. (A) Specific binding of KP7 TCR to HLA-A2-VLH (solid line), with control (HLA-B7-TPR) and HLA-A2-VLR signals also shown (dashed and dotted lines, respectively). (B) Equilibrium affinity analysis of TCR/HLA-A2-VLH interaction. Scatchard plot is shown inset.

Figures were selected by an automated process.