How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire
| Autor: | Michael I. Nishimura, Yuan Wang, Brian G. Pierce, Sydney J. Blevins, Nishant K. Singh, Timothy T. Spear, Timothy P. Riley, Zhiping Weng, Brian M. Baker |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Protein Conformation media_common.quotation_subject Receptors Antigen T-Cell alpha-beta Static Electricity chemical and pharmacologic phenomena Computational biology Biology Major histocompatibility complex Adaptability Class I MHC protein 03 medical and health sciences 0302 clinical medicine HLA-A2 Antigen Humans Receptor Gene media_common Genetics Multidisciplinary T-cell receptor hemic and immune systems MHC restriction Tcr repertoire 030104 developmental biology PNAS Plus biology.protein 030215 immunology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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