The autoimmune TCR-Ob 2F3 can bind to MBP85-99/HLA-DR2 having an unconventional mode as in TCR-Ob 1A12
Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02193, USA. Molecular Immunology
(Impact Factor: 2.97).
11/2010; 48(1-3):314-20. DOI: 10.1016/j.molimm.2010.07.010
The generation of T cell receptor (TCR) sequence diversity can produce 'forbidden' clones able to recognize self-antigens. Here, the structure of the complex between a myelin basic protein peptide (MBP85-99), human leukocyte antigen (HLA)-DR2 (DRB1*1501/DRA) and TCR-Ob.2F3, the dominant autoimmune clone obtained from a multiple sclerosis (MS) patient, has been determined using structural docking simulation and dynamics in silico and compared to the structure of TCR-Ob.1A12 complexes with the same MHC/peptide determined by X-ray crystallography. The two TCRs differ by three amino acids in the CDR3 α and β loops. As the result different hydrogen bonds are formed between the two CDR3β loops and the peptide in the complexes of the simulated structures, with three hydrogen bonds seen in the TCR-Ob.2F3 complex and five in the TCR-Ob.1A12 complex. The two TCRs, each located near the N-terminal end of the HLA-DR2 binding groove and both had an orthogonal binding axis but they deviated by about 10°. Simulation methods, such as structural docking and molecular dynamics as used here, provide an avenue to understand molecular binding mode efficiently and more rapidly than obtaining multiple crystal structures when a large structural database is already available.
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- "d that portion of MHCII which surrounds that part of the peptide . Hence the TCR rotated is heavily tilted to - wards what is normally illustrated to be the left hand end of the MHC protein ( Fig . 2 ) . Recent work on TCRs , Ob . 2F3 and Ob . 3D1 , from one of the same donors indicated that these TCRs also bind the N terminal end of the peptide ( Kato et al . , 2010 ) . These TCRs may have low affinity for their self MHC / self peptide ligands , however , they may also escape tolerance mechanisms in the thymus because their angle of approach to MHC lowers the ability of CD4 to contribute to signaling within the T cell ( Adams et al . , 2011 ; Yin et al . , 2012a ) . Another version of engagement of"
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ABSTRACT: T cell recognition of foreign peptide antigen and tolerance to self peptides is key to the proper function of the immune system. Usually, in the thymus T cells that recognize self MHC + self peptides are deleted and those with the potential to recognize self MHC + foreign peptides are selected to mature. However there are exceptions to these rules. Autoimmunity and allergy are two of the most common immune diseases that can be related to recognition of self. Many genes work together to lead to autoimmunity. Of those, particular MHC alleles are the most strongly associated, reflecting the key importance of MHC presentation of self peptides in autoimmunity. T cells specific for combinations of self MHC and self peptides may escape thymus deletion, and thus be able to drive autoimmunity, for several reasons: the relevant self peptide may be presented at low abundance in the thymus but at high level in particular peripheral tissues; the relevant self peptide may bind to MHC in an unusual register, not present in the thymus but apparent elsewhere; finally the relevant self peptide may be post translationally modified in a tissue specific fashion. In some types of allergy, the peptide + MHC combination may also be fully derived from self. However the combination in question may be modified by the presence of other ligands, such as small drug molecules or metal ions. Thus these types of allergies may act like the post translationally modified peptides involved some types of autoimmunity.
Protein & Cell 01/2013; 4(1):8-16. DOI:10.1007/s13238-012-2077-7 · 3.25 Impact Factor
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ABSTRACT: Sweet's syndrome (acute febrile neutrophilic dermatosis) is characterized by fever, polymorphonuclear leukocytosis of blood, painful plaques on the limbs, face and neck, and histologically a dense dermal infiltration with mature neutrophils. Sweet's syndrome is often a complication of hematologic malignant disease or drug-induced sensitivity reactions and has a significant susceptibility correlated with certain human leukocyte antigen (HLA).
A 5-week-old Japanese girl with Sweet's syndrome confirmed by skin biopsy was successfully treated and HLA analysis was performed.
The patient was one of the youngest patients reported with Sweet's syndrome, suggesting the importance of the genetic background. Although the HLA types of the patient did not have B54, which was reported as a significant susceptibility correlation, structural analysis of the patient's HLAs suggested a similar possible motif for the bound peptides.
Studies on the HLA bound peptides and HLA structural analysis for patients with Sweet's syndrome would be valuable for understanding the molecular mechanism of the pathogenesis.
World Journal of Pediatrics 08/2011; 8(2):181-4. DOI:10.1007/s12519-011-0308-2 · 1.05 Impact Factor
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ABSTRACT: T cell receptors (TCRs) are immune proteins that specifically bind to antigenic molecules, which are often foreign peptides presented by Major Histocompatibility Complex proteins (pMHCs), playing a key role in the cellular immune response.To advance our understanding and modelingofthis dynamic immunological event, we assembled a protein-protein docking benchmark consisting of20 structures of crystallized TCR/pMHC complexes for which unbound structures exist for both TCR and pMHC. We used our benchmark to comparepredictive performanceusing several flexible and rigid backboneTCR/pMHC docking protocols. Our flexible TCR docking algorithm, TCRFlexDock, improved predictive success over the fixed backbone protocol, leadingto near-native predictions for 80% of the TCR/pMHC cases among the top 10 models, and 100% of the cases in the top 30 models. We then appliedTCRFlexDockto predict the twodistinct docking modes recently described for a single TCR bound to two different antigens, andtested several protein modeling scoring functionsfor prediction ofTCR/pMHCbinding affinities. Thisalgorithm and benchmarkwill facilitate further progress toward the simulation, prediction and design of uncharacterized TCR/pMHC complexes.
Protein Science 01/2013; 22(1). DOI:10.1002/pro.2181 · 2.85 Impact Factor
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