How structural adaptability exists alongside HLA-A2 bias in the human alphabeta TCR repertoire
Authors
Blevins, Sydney J.Pierce, Brian G.
Singh, Nishant K.
Riley, Timothy P.
Wang, Yuan
Spear, Timothy T.
Nishimura, Michael I.
Weng, Zhiping
Baker, Brian M.
UMass Chan Affiliations
Program in Bioinformatics and Integrative BiologyDocument Type
Journal ArticlePublication Date
2016-03-01Keywords
MHC biasT-cell receptor
binding
peptide/MHC
structure
Amino Acids, Peptides, and Proteins
Bioinformatics
Cells
Chemical Actions and Uses
Computational Biology
Immunology and Infectious Disease
Investigative Techniques
Structural Biology
Metadata
Show full item recordAbstract
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 alphabeta 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 alpha1-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 Valpha and Vbeta 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.Source
Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):E1276-85. doi: 10.1073/pnas.1522069113. Epub 2016 Feb 16. Link to article on publisher's site
DOI
10.1073/pnas.1522069113Permanent Link to this Item
http://hdl.handle.net/20.500.14038/25946PubMed ID
26884163Related Resources
Rights
Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1522069113