4AEN

HLA-DR1 with covalently linked CLIP106-120 in reversed orientation

Summary for 4AEN

• Entry DOI: 10.2210/pdb4aen/pdb
• Related: 1A6A 1AQD 1D5M 1D5X 1D5Z 1D6E 1DLH 1FV1 1FYT 1H15 1HXY 1ICF 1IIE 1J8H 1JWM 1JWS 1JWU 1KG0 1KLG 1KLU 1L3H 1LO5 1MUJ 1SEB 1SJE 1SJH 1T5W 1T5X 1YMM 1ZGL 2G9H 2SEB 2XN9 4AH2
• Descriptor: HLA CLASS II HISTOCOMPATIBILITY ANTIGEN, DR ALPHA CHAIN, HLA CLASS II HISTOCOMPATIBILITY ANTIGEN, DRB1-1 BETA CHAIN, HLA CLASS II HISTOCOMPATIBILITY ANTIGEN GAMMA CHAIN, ... (5 entities in total)
• Functional Keywords: immune system, self antigen, invariant chain, clip
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cell membrane; Single-pass type I membrane protein: P01903 P04229; Cell membrane; Single-pass type II membrane protein (Potential): P04233
• Total number of polymer chains: 3
• Total formula weight: 48305.32

Authors

Schlundt, A.,Guenther, S.,Sticht, J.,Wieczorek, M.,Roske, Y.,Heinemann, U.,Freund, C. (deposition date: 2012-01-11, release date: 2012-08-01, Last modification date: 2024-10-16)

Primary citation

Schlundt, A.,Gunther, S.,Sticht, J.,Wieczorek, M.,Roske, Y.,Heinemann, U.,Freund, C.
Peptide Linkage to the Alpha-Subunit of Mhcii Creates a Stably Inverted Antigen Presentation Complex.
J.Mol.Biol., 423:294-, 2012

PubMed Abstract: Class II proteins of the major histocompatibility complex (MHCII) typically present exogenous antigenic peptides to cognate T cell receptors of CD4-T lymphocytes. The exact conformation of peptide-MHCII complexes (pMHCII) can vary depending on the length, register and orientation of the bound peptide. We have recently found the self-peptide CLIP (class-II-associated invariant chain-derived peptide) to adopt a dynamic bidirectional binding mode with regard to the human MHCII HLA-DR1 (HLA, human leukocyte antigen). We suggested that inversely bound peptides could activate specific T cell clones in the context of autoimmunity. As a first step to prove this hypothesis, pMHC complexes restricted to either the canonical or the inverted peptide orientation have to be constructed. Here, we show that genetically encoded linkage of CLIP and two other antigenic peptides to the HLA-DR1 α-chain results in stable complexes with inversely bound ligands. Two-dimensional NMR and biophysical analyses indicate that the CLIP-bound pMHC(inv) complex (pMHC(inv), inverted MHCII-peptide complex) displays high thermodynamic stability but still allows for the exchange against higher-affinity viral antigen. Complemented by comparable data on a corresponding β-chain-fused canonical HLA-DR1/CLIP complex, we further show that linkage of CLIP leads to a binding mode exactly the same as that of the corresponding unlinked constructs. We suggest that our approach constitutes a general strategy to create pMHC(inv) complexes. Such engineering is needed to create orientation-specific antibodies and raise T cells to study phenomena of autoimmunity caused by isomeric pMHCs.

PubMed: 22820093
DOI: 10.1016/J.JMB.2012.07.008

Experimental method

X-RAY DIFFRACTION (2.2 Å)