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

Lan, Huan, Abualrous, Esam T., Sticht, Jana, Fernandez, Laura Maria Arroyo, Werk, Tamina, Weise, Christoph, Ballaschk, Martin, Schmieder, Peter, Loll, Bernhard and Freund, Christian – 2021

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 ?2-1-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.

Title
Exchange_Lan
Author
Lan, Huan, Abualrous, Esam T., Sticht, Jana, Fernandez, Laura Maria Arroyo, Werk, Tamina, Weise, Christoph, Ballaschk, Martin, Schmieder, Peter, Loll, Bernhard and Freund, Christian
Date
2021-07-09
Identifier
10.1038/s41467-021-24401-4
Source(s)
Appeared in
Nature Communications - Volume 12, Issue 1
Language
eng
Type
Text