Partial dissociation of truncated peptides influences the structural dynamics of the MHCI binding groove
- Antigen processing on MHCI involves the exchange of low-affinity peptides by high-affinity, immunodominant ones. This peptide editing process is mediated by tapasin and ERAAP at the peptide C- and N-terminus, respectively. Since tapasin does not contact the peptide directly, a sensing mechanism involving conformational changes likely allows tapasin to distinguish antigen-loaded MHCI molecules from those occupied by weakly bound, non-specific peptides. To understand this mechanism at the atomic level, we performed molecular dynamics simulations of MHCI allele B*44:02 loaded with peptides truncated or modified at the C- or N-terminus. We show that the deletion of peptide anchor residues leads to reversible, partial dissociation of the peptide from MHCI on the microsecond timescale. Fluctuations in the MHCI \(\alpha_{2−1}\) helix segment, bordering the binding groove and cradled by tapasin in the PLC, are influenced by the peptide C-terminus occupying the nearby F-pocket. Simulations of tapasin complexed with MHCI bound to a low-affinity peptide show that tapasin widens the MHCI binding groove near the peptide C-terminus and weakens the attractive forces between MHCI and the peptide. Our simulations thus provide a detailed, spatially resolved picture of MHCI plasticity, revealing how peptide loading status can affect key structural regions contacting tapasin.
Author: | Olivier Jean FisetteGND, Sebastian WingbermühleGND, Lars V. SchäferORCiDGND |
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URN: | urn:nbn:de:hbz:294-70347 |
DOI: | https://doi.org/10.3389/fimmu.2017.00408 |
Parent Title (English): | Frontiers in immunology |
Publisher: | Frontiers Media |
Place of publication: | Lausanne |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2020/03/04 |
Date of first Publication: | 2017/04/18 |
Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
Tag: | antigen; major histocompatibility complex class I (MHCI); molecular dynamics (MD) simulations; peptide editing; peptide loading complex (PLC); protein dynamics |
Volume: | 8 |
First Page: | 408-1 |
Last Page: | 408-12 |
Institutes/Facilities: | Lehrstuhl für Theoretische Chemie |
open_access (DINI-Set): | open_access |
faculties: | Fakultät für Chemie und Biochemie |
Licence (English): | Creative Commons - CC BY 4.0 - Attribution 4.0 International |