4aen
From Proteopedia
HLA-DR1 with covalently linked CLIP106-120 in reversed orientation
Structural highlights
DiseaseHG2A_HUMAN Note=A chromosomal aberration involving CD74 is found in a non-small cell lung tumor. Results in the formation of a CD74-ROS1 chimeric protein.[1] FunctionHG2A_HUMAN Plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II takes place. Serves as cell surface receptor for the cytokine MIF. Publication Abstract from PubMedClass II proteins of the major histocompatibility complex (MHCII) typically present exogenous antigenic peptides to cognate T cell receptors of 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 alpha-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 beta-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. Peptide Linkage to the alpha-Subunit of MHCII Creates a Stably Inverted Antigen Presentation Complex.,Schlundt A, Gunther S, Sticht J, Wieczorek M, Roske Y, Heinemann U, Freund C J Mol Biol. 2012 Jul 20. PMID:22820093[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Freund C | Guenther S | Heinemann U | Roske Y | Schlundt A | Sticht J | Wieczorek M