Exchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules

Huan Lan, Esam T. Abualrous, Jana Sticht, Laura Maria Arroyo Fernandez, Tamina Werk, Christoph Weise, Martin Ballaschk, Peter Schmieder, Bernhard Loll and Christian Freund ()
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Huan Lan: Freie Universität Berlin
Esam T. Abualrous: Freie Universität Berlin
Jana Sticht: Freie Universität Berlin
Laura Maria Arroyo Fernandez: Freie Universität Berlin
Tamina Werk: Freie Universität Berlin
Christoph Weise: Freie Universität Berlin
Martin Ballaschk: Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Peter Schmieder: Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Bernhard Loll: Freie Universität Berlin
Christian Freund: Freie Universität Berlin

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract The repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface is tailored by the ER-resident peptide loading complex (PLC), which contains the exchange catalyst tapasin. Tapasin stabilizes MHC-I molecules and promotes the formation of stable peptide-MHC-I (pMHC-I) complexes that serve as T cell antigens. Exchange of suboptimal by high-affinity ligands is catalyzed by tapasin, but the underlying mechanism is still elusive. Here we analyze the tapasin-induced changes in MHC-I dynamics, and find the catalyst to exploit two essential features of MHC-I. First, tapasin recognizes a conserved allosteric site underneath the α2-1-helix of MHC-I, ‘loosening’ the MHC-I F-pocket region that accomodates the C-terminus of the peptide. Second, the scoop loop11–20 of tapasin relies on residue L18 to target the MHC-I F-pocket, enabling peptide exchange. Meanwhile, tapasin residue K16 plays an accessory role in catalysis of MHC-I allotypes bearing an acidic F-pocket. Thus, our results provide an explanation for the observed allele-specificity of catalyzed peptide exchange.

Date: 2021
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DOI: 10.1038/s41467-021-24401-4

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