Recognition dynamics of cancer mutations on the ERp57-tapasin interface

Monikaben Padariya , Umesh Kalathiya , Douglas Houston , Javier Alfaro

Abstract

Down regulation of the major histocompatibility class (MHC) I pathway plays an important role in tumour development, and can be achieved by suppression of HLA expression or mutations in the MHC peptide-binding pocket. The peptide-loading complex (PLC) loads peptides on the MHC-I molecule in a dynamic multi-step assembly process. The effects of cancer variants on ERp57 and tapasin components from the MHC-I pathway is less known, and they could have an impact on antigen presentation. Applying computational approaches, we analysed whether the ERp57-tapasin binding might be altered by missense mutations. The variants H408R(ERp57) and P96L, D100A, G183R(tapasin) at the protein–protein interface improved protein stability (ΔΔG) during the initial screen of 14 different variants. The H408R(ERp57) and P96L(tapasin) variants, located close to disulphide bonds, were further studied by molecular dynamics (MD). Identifying intramolecular a-a’ domain interactions, MD revealed open and closed conformations of ERp57 in the presence and absence of tapasin. In wild-type and mutant ERp57-tapasin complexes, residues Val97, Ser98, Tyr100, Trp405, Gly407(ERp57) and Asn94, Cys95, Arg97, Asp100(tapasin) formed common H-bond interactions. Moreover, comparing the H-bond networks for P96L and H408R with each other, suggests that P96L(tapasin) improved ERp57-tapasin binding more than the H408R(ERp57) mutant. During MD, the C-terminus domain (that binds MHC-I) in tapasin from the ERp57(H408R)-tapasin complex moved away from the PLC, whereas in the ERp57-tapasin(P96L) system was oppositely displaced. These findings can have implications for the function of PLC and, ultimately, for the presentation of MHC-I peptide complex on the tumour cell surface.
Author Monikaben Padariya (ICCVS)
Monikaben Padariya,,
- International Centre for Cancer Vaccine Science
, Umesh Kalathiya (ICCVS)
Umesh Kalathiya,,
- International Centre for Cancer Vaccine Science
, Douglas Houston
Douglas Houston,,
-
, Javier Alfaro (ICCVS)
Javier Alfaro,,
- International Centre for Cancer Vaccine Science
Journal seriesCancers, ISSN 2072-6694, (N/A 140 pkt)
Issue year2020
Vol12
No3
Pages1-20
Publication size in sheets0.95
Article number737
Keywords in Englishtapasin, ERp57, MHC-I, peptide loading complex, molecular dynamics, stability change, cBioPortal, protein-protein interactions, cancer mutations
ASJC Classification2730 Oncology; 1306 Cancer Research
DOIDOI:10.3390/cancers12030737
URL https://www.mdpi.com/2072-6694/12/3/737
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 08-04-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.44; WoS Impact Factor: 2018 = 6.162 (2)
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