T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions
T-cell receptors are an important part in the adaptive immune system as they are responsible for detecting foreign proteins presented by the major histocompatibility complex (MHC). The affinity is predominantly determined by structure and sequence of the complementarity determining regions (CDRs), o...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-07-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01440/full |
| _version_ | 1818149226522083328 |
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| author | Monica L. Fernández-Quintero Nancy D. Pomarici Johannes R. Loeffler Clarissa A. Seidler Klaus R. Liedl |
| author_facet | Monica L. Fernández-Quintero Nancy D. Pomarici Johannes R. Loeffler Clarissa A. Seidler Klaus R. Liedl |
| author_sort | Monica L. Fernández-Quintero |
| collection | DOAJ |
| description | T-cell receptors are an important part in the adaptive immune system as they are responsible for detecting foreign proteins presented by the major histocompatibility complex (MHC). The affinity is predominantly determined by structure and sequence of the complementarity determining regions (CDRs), of which the CDR3 loops are responsible for peptide recognition. We present a kinetic classification of T-cell receptor CDR3 loops with different loop lengths into canonical and non-canonical solution structures. Using molecular dynamics simulations, we do not only sample available X-ray structures, but we also observe a substantially broader CDR3 loop ensemble with various distinct kinetic minima in solution. Our results strongly imply, that for given CDR3 loop sequences several canonical structures have to be considered to characterize the conformational diversity of these loops. Our suggested dominant solution structures could extend the repertoire of available canonical clusters by including kinetic minimum structures present in solution. Thus, the CDR3 loops need to be characterized as conformational ensembles in solution. Furthermore, the conformational changes of the CDR3 loops follow the paradigm of conformational selection, because the experimentally determined binding competent state is present within this ensemble of pre-existing conformations without the presence of the antigen. We also identify strong correlations between the CDR3 loops and include combined state descriptions. Additionally, we observe a strong dependency of the CDR3 loop conformations on the relative Vα-Vβ interdomain orientations, revealing that certain CDR3 loop states favor specific interface orientations. |
| first_indexed | 2024-12-11T13:03:40Z |
| format | Article |
| id | doaj.art-512582b50af24d909b1a7ae0e476671c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T13:03:40Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-512582b50af24d909b1a7ae0e476671c2022-12-22T01:06:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-07-011110.3389/fimmu.2020.01440545327T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain DistributionsMonica L. Fernández-QuinteroNancy D. PomariciJohannes R. LoefflerClarissa A. SeidlerKlaus R. LiedlT-cell receptors are an important part in the adaptive immune system as they are responsible for detecting foreign proteins presented by the major histocompatibility complex (MHC). The affinity is predominantly determined by structure and sequence of the complementarity determining regions (CDRs), of which the CDR3 loops are responsible for peptide recognition. We present a kinetic classification of T-cell receptor CDR3 loops with different loop lengths into canonical and non-canonical solution structures. Using molecular dynamics simulations, we do not only sample available X-ray structures, but we also observe a substantially broader CDR3 loop ensemble with various distinct kinetic minima in solution. Our results strongly imply, that for given CDR3 loop sequences several canonical structures have to be considered to characterize the conformational diversity of these loops. Our suggested dominant solution structures could extend the repertoire of available canonical clusters by including kinetic minimum structures present in solution. Thus, the CDR3 loops need to be characterized as conformational ensembles in solution. Furthermore, the conformational changes of the CDR3 loops follow the paradigm of conformational selection, because the experimentally determined binding competent state is present within this ensemble of pre-existing conformations without the presence of the antigen. We also identify strong correlations between the CDR3 loops and include combined state descriptions. Additionally, we observe a strong dependency of the CDR3 loop conformations on the relative Vα-Vβ interdomain orientations, revealing that certain CDR3 loop states favor specific interface orientations.https://www.frontiersin.org/article/10.3389/fimmu.2020.01440/fullCDR3 loop ensemblesconformational selectionMarkov-state modelsrelative Vα/Vβ domain distributionsT-cell receptorsT-cell receptor structure and design |
| spellingShingle | Monica L. Fernández-Quintero Nancy D. Pomarici Johannes R. Loeffler Clarissa A. Seidler Klaus R. Liedl T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions Frontiers in Immunology CDR3 loop ensembles conformational selection Markov-state models relative Vα/Vβ domain distributions T-cell receptors T-cell receptor structure and design |
| title | T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions |
| title_full | T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions |
| title_fullStr | T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions |
| title_full_unstemmed | T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions |
| title_short | T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions |
| title_sort | t cell receptor cdr3 loop conformations in solution shift the relative vα vβ domain distributions |
| topic | CDR3 loop ensembles conformational selection Markov-state models relative Vα/Vβ domain distributions T-cell receptors T-cell receptor structure and design |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01440/full |
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