title: How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire.
abstract: How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining αβ TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the α1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Vα and Vβ genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556;
authors.forename: Sydney J
authors.initials: SJ
authors.lastname: Blevins
authors.affiliation: University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850;
authors.forename: Brian G
authors.initials: BG
authors.lastname: Pierce
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556;
authors.forename: Nishant K
authors.initials: NK
authors.lastname: Singh
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556;
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Riley
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, IL 60153; Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153;
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Spear
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, IL 60153; Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153;
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556; brian-baker@nd.edu.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Baker
mesh_terms: D015789:HLA-A2 Antigen / Q000737:chemistry*; D006801:Humans; D011487:Protein Conformation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry*; D055672:Static Electricity
chemical_list: D015789:HLA-A2 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: MHC bias; T-cell receptor; binding; peptide/MHC; structure