Impact of HLA-DR antigen binding cleft rigidity on T cell recognition
journal contributionposted on 08.02.2021, 00:45 authored by C Szeto, JI Bloom, H Sloane, CA Lobos, J Fodor, D Jayasinghe, Demetra SM Chatzileontiadou, EJ Grant, AM Buckle, S Gras
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. The interaction between T cell receptor (TCR) and peptide (p)-Human Leukocyte Antigen (HLA) complexes is the critical first step in determining T cell responses. X-ray crystallographic studies of pHLA in TCR-bound and free states provide a structural perspective that can help understand T cell activation. These structures represent a static “snapshot”, yet the nature of pHLAs and their interactions with TCRs are highly dynamic. This has been demonstrated for HLA class I molecules with in silico techniques showing that some interactions, thought to stabilise pHLA-I, are only transient and prone to high flexibility. Here, we investigated the dynamics of HLA class II molecules by focusing on three allomorphs (HLA-DR1,-DR11 and-DR15) that are able to present the same epitope and activate CD4+ T cells. A single TCR (F24) has been shown to recognise all three HLA-DR molecules, albeit with different affinities. Using molecular dynamics and crystallographic ensemble refinement, we investigate the molecular basis of these different affinities and uncover hidden roles for HLA polymorphic residues. These polymorphisms were responsible for the widening of the antigen binding cleft and disruption of pHLA-TCR interactions, underpinning the hierarchy of F24 TCR binding affinity, and ultimately T cell activation. We expanded this approach to all available pHLA-DR structures and discovered that all HLA-DR molecules were inherently rigid. Together with in vitro protein stability and peptide affinity measurements, our results suggest that HLA-DR1 possesses inherently high protein stability, and low HLA-DM susceptibility.
This work was funded by the Australian National Health and Medical Research Council (NHMRC), E.J.G. is a NHMRC CJ Martin Fellow (#1110429), S.G. is a NHMRC SRF-A Fellow (#1159272).
JournalInternational Journal of Molecular Sciences
PublisherMultidisciplinary Digital Publishing Institute (MDPI)
Rights StatementThe Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.
Science & TechnologyLife Sciences & BiomedicinePhysical SciencesBiochemistry & Molecular BiologyChemistry, MultidisciplinaryChemistryhuman leukocyte antigen (HLA)MHC class IIpeptide bindingprotein stabilitymolecular dynamicsensemble refinementTCR bindingMHC CLASS-IIPEPTIDE-BINDINGDM-SUSCEPTIBILITYKINETIC STABILITYCRYSTAL-STRUCTURESTRUCTURAL BASISMOLECULAR-BASISPROTEINCOMPLEXESCHAINChemical Physics