PXD008500

PXD008500 is an original dataset announced via ProteomeXchange.

Title	Ranking the contribution of ankylosing spondylitis-associated ERAP1 polymorphisms to shaping the HLA-B*27 peptidome
Description	The Endoplasmic reticulum aminopeptidase I (ERAP1) trims peptides to their optimal size for binding to Major Histocompatibility Complex class I proteins. The natural polymorphism of this enzyme is associated with ankylosing spondylitis (AS) in epistasis with the major risk factor for this disease, HLA-B*27, suggesting a direct relationship between AS and HLA-B*27-bound peptides. Three polymorphisms that affect peptide trimming protect from AS: K528R, D575N/R725Q, and Q730E. We characterized and ranked the effects of each mutation, and their various combinations, by quantitative comparisons of the HLA-B*27 peptidomes from cells expressing distinct ERAP1 variants. Five features were examined: peptide length, N-terminal flanking residues, N-terminal residues of the natural ligands, internal sequences and affinity for B*27:05. Polymorphism at residue 528 showed the largest influence, affecting all five features regardless of peptide length. D575N/R725Q showed a much smaller effect. Yet, when co-occurring with K528R, it added to this latter change in decreasing ERAP1 activity. Polymorphism at residue 730 showed a significant influence on peptide length, reflecting differential trimming of nonamers and longer peptides. Accordingly, multiple features were affected by the Q730E mutation in a length-dependent way. The alterations induced in the B*27:05 peptidome by natural ERAP1 variants with different K528R/Q730E combinations reflected separate and additive effects of both mutations. Thus, the influence of ERAP1 on HLA-B*27 is very diverse at the population level, due to the multiplicity and complexity of ERAP1 variants, and to the distinct effects of their co-occurring polymorphisms, leading to significant modulation of disease risk among HLA-B*27-positive individuals.
HostingRepository	PRIDE
AnnounceDate	2018-04-10
AnnouncementXML	Submission_2018-04-20_05:25:43.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Arie Admon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-12-19 05:15:09	ID requested
1	2018-04-10 05:56:13	announced
⏵ 2	2018-04-20 05:25:44	announced	Updated publication reference for PubMed record(s): 29632046.

Sanz-Bravo A, Alvarez-Navarro C, Mart, í, n-Esteban A, Barnea E, Admon A, L, ó, pez de Castro JA, Ranking the Contribution of Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphisms to Shaping the HLA-B*27 Peptidome. Mol Cell Proteomics, 17(7):1308-1323(2018) [pubmed]

curator keyword: Biomedical

submitter keyword: human, HLA, MHC, peptidome, immunopeptidome, LC-MS/MS

Arie Admon
contact affiliation	Technion, Israel institute of technology
contact email	admon@technion.ac.il
lab head
Arie Admon
contact affiliation	Biology
contact email	admon@tx.technion.ac.il
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD008500
     1. Label: PRIDE project
     2. Name: Ranking the contribution of ankylosing spondylitis-associated ERAP1 polymorphisms to shaping the HLA-B*27 peptidome