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Title: An Engineered Switch in T Cell Receptor Specificity Leads to an Unusual but Functional Binding Geometry

Journal Article · · Structure
 [1];  [2];  [1];  [1];  [3];  [1];  [1];  [2]
  1. Univ. of Illinois, Urbana, IL (United States)
  2. Univ. of Notre Dame, IN (United States)
  3. Univ. of Kentucky, Lexington, KY (United States)
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Utilizing a diverse binding site, T cell receptors (TCRs) specifically recognize a composite ligand comprised of a foreign peptide and a major histocompatibility complex protein (MHC). To help understand the determinants of TCR specificity, we studied a parental and engineered receptor whose peptide specificity had been switched via molecular evolution. Altered specificity was associated with a significant change in TCR-binding geometry, but this did not impact the ability of the TCR to signal in an antigen-specific manner. The determinants of binding and specificity were distributed among contact and non-contact residues in germline and hypervariable loops, and included disruption of key TCR-MHC interactions that bias αβ TCRs toward particular binding modes. Sequence-fitness landscapes identified additional mutations that further enhanced specificity. Furthermore, our results demonstrate that TCR specificity arises from the distributed action of numerous sites throughout the interface, with significant implications for engineering therapeutic TCRs with novel and functional recognition properties.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Institutes of Health (NIH)
Grant/Contract Number:
GM118166; CA178844; CA180723
OSTI ID:
1267463
Journal Information:
Structure, Vol. 24, Issue 7; ISSN 0969-2126
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 16 works
Citation information provided by
Web of Science

References (29)

T Cell Receptor Signaling Is Limited by Docking Geometry to Peptide-Major Histocompatibility Complex journal November 2011
Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity journal November 2015
Identification and engineering of human variable regions that allow expression of stable single-chain T cell receptors journal December 2010
Structural and dynamic control of T-cell receptor specificity, cross-reactivity, and binding mechanism journal October 2012
T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex journal October 2015
How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire journal February 2016
Directed evolution of antibody fragments with monovalent femtomolar antigen-binding affinity journal September 2000
T Cell Receptor Cross-reactivity Directed by Antigen-Dependent Tuning of Peptide-MHC Molecular Flexibility journal December 2009
TCRs Used in Cancer Gene Therapy Cross-React with MART-1/Melan-A Tumor Antigens via Distinct Mechanisms journal July 2011
Germ Line-governed Recognition of a Cancer Epitope by an Immunodominant Human T-cell Receptor journal July 2009
Increased peptide contacts govern high affinity binding of a modified TCR whilst maintaining a native pMHC docking mode journal January 2013
Four A6-TCR/Peptide/HLA-A2 Structures that Generate Very Different T Cell Signals Are Nearly Identical journal July 1999
Measuring the activity of protein variants on a large scale using deep mutational scanning journal August 2014
T Cell Receptor Recognition via Cooperative Conformational Plasticity journal October 2006
Quantitative Analysis of the Contribution of TCR/pepMHC Affinity and CD8 to T Cell Activation journal February 2003
In vitro evolution of a T cell receptor with high affinity for peptide/MHC journal April 2000
Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma journal August 2013
Understanding the complexity and malleability of T-cell recognition journal January 2015
The basis for limited specificity and MHC restriction in a T cell receptor interface journal June 2013
A flexible docking approach for prediction of T cell receptor-peptide-MHC complexes journal December 2012
Computational Design of the Affinity and Specificity of a Therapeutic T Cell Receptor journal February 2014
Computational Design of a Protein-Based Enzyme Inhibitor journal September 2013
Generation of peptide–MHC class I complexes through UV-mediated ligand exchange journal August 2006
How tcrs bind Mhcs, Peptides, and Coreceptors journal April 2006
Yeast polypeptide fusion surface display levels predict thermal stability and soluble secretion efficiency journal October 1999
Crystal Structures of Two Closely Related but Antigenically Distinct HLA-A2/Melanocyte-Melanoma Tumor-Antigen Peptide Complexes journal September 2001
Plasticity in the Contribution of T Cell Receptor Variable Region Residues to Binding of Peptide–HLA-A2 Complexes journal November 2013
Changing the peptide specificity of a human T-cell receptor by directed evolution journal November 2014
A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control journal August 2014

Cited By (3)

Mapping Interaction Sites on Human Chemokine Receptors by Deep Mutational Scanning journal April 2018
Subtle changes at the variable domain interface of the T-cell receptor can strongly increase affinity journal December 2017
Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes journal September 2017

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59 BASIC BIOLOGICAL SCIENCES