Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis |
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| Authors: | Holm Lotta Bockermann Robert Wellner Erik Bäcklund Johan Holmdahl Rikard Kihlberg Jan |
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| Institution: | 1. Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden;2. Section of Medical Inflammation Research, Lund University, Sölvegatan 19, I11 BMC, SE-221 84 Lund, Sweden;3. AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden;1. Unidad de Biofísica (CSIC, UPV/EHU), and Departamento de Bioquímica, Universidad del País Vasco, Aptdo. 644, 48080 Bilbao, Spain;2. OWL, Parque Tecnológico de Bizkaia, Bizkaia, Spain;1. Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada, Spain;2. Institute for Research in Biomedicine, University of Barcelona and CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Barcelona, Spain;1. Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;2. Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;3. Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;4. Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;1. Department of Applied Biological Chemistry, Faculty of Agriculture, Graduate School of Science and Technology, Japan;2. Center for Transdisciplinary Research, Niigata University, 2-8050 Ikarashi, Nishi-Ku, Niigata 950-2181, Japan;1. Jilin Province Key Laboratory on Chemistry and Biology of Natural Drugs in Changbai Mountain, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China;2. School of Biological Science and Technology, University of Jinan, Jinan 250022, PR China |
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| Abstract: | Collagen induced arthritis (CIA) is the most studied animal model for rheumatoid arthritis and is associated with the MHC class II molecule Aq. T-cell recognition of a peptide from type II collagen, CII256-270, bound to Aq is a requirement for development of CIA. Lysine 264 is the major T-cell recognition site of CII256-270 and CIA is in particular associated with recognition of lysine 264 after posttranslational hydroxylation and subsequent attachment of a beta-D-galactopyranosyl moiety. In this paper we have studied the structural requirements of collagenous glycopeptides required for T-cell stimulation, as an extension of earlier studies of the recognition of the galactose moiety. Synthesis and evaluation of alanine substituted glycopeptides revealed that there are T-cells that only recognise the galactosylated hydroxylysine 264, and no other amino acid side chains in the peptide. Other T-cells also require glutamic acid 266 as a T-cell contact point. Introduction of a methylene ether isostere instead of the amide bond between residues 260 and 261 allowed weaker recognition by some, but not all, of the T-cells. Altogether, these results allowed us to propose a model for glycopeptide recognition by the T-cells, where recognition from one or the other side of the galactose moiety could explain the different binding patterns of the T-cells. |
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