F pocket flexibility influences the tapasin dependence of two differentially disease-associated MHC Class I proteins

Esam T. Abualrous, Susanne Fritzsche, Zeynep Hein, Mohammed S. Al-Balushi, Peter Reinink, Louise H. Boyle, Ursula Wellbrock, Antony N. Antoniou, Sebastian Springer

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide-binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype.

Original languageEnglish
Pages (from-to)1248-1257
Number of pages10
JournalEuropean Journal of Immunology
Volume45
Issue number4
DOIs
Publication statusPublished - Apr 1 2015

Fingerprint

HLA-B Antigens
Amino Acids
Peptides
Protein Stability
Ankylosing Spondylitis
Computer Simulation
Proteins
Binding Sites
tapasin
F-chemotactic peptide
IgA receptor

Keywords

  • Ankylosing spondylitis
  • HLA-B27
  • Major histocompatibility complex
  • Molecular dynamics
  • Natively unstructured proteins
  • Protein folding
  • Simulations

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

F pocket flexibility influences the tapasin dependence of two differentially disease-associated MHC Class I proteins. / Abualrous, Esam T.; Fritzsche, Susanne; Hein, Zeynep; Al-Balushi, Mohammed S.; Reinink, Peter; Boyle, Louise H.; Wellbrock, Ursula; Antoniou, Antony N.; Springer, Sebastian.

In: European Journal of Immunology, Vol. 45, No. 4, 01.04.2015, p. 1248-1257.

Research output: Contribution to journalArticle

Abualrous, ET, Fritzsche, S, Hein, Z, Al-Balushi, MS, Reinink, P, Boyle, LH, Wellbrock, U, Antoniou, AN & Springer, S 2015, 'F pocket flexibility influences the tapasin dependence of two differentially disease-associated MHC Class I proteins', European Journal of Immunology, vol. 45, no. 4, pp. 1248-1257. https://doi.org/10.1002/eji.201445307
Abualrous, Esam T. ; Fritzsche, Susanne ; Hein, Zeynep ; Al-Balushi, Mohammed S. ; Reinink, Peter ; Boyle, Louise H. ; Wellbrock, Ursula ; Antoniou, Antony N. ; Springer, Sebastian. / F pocket flexibility influences the tapasin dependence of two differentially disease-associated MHC Class I proteins. In: European Journal of Immunology. 2015 ; Vol. 45, No. 4. pp. 1248-1257.
@article{547b5df1da1144a98b9c75e2b44adc39,
title = "F pocket flexibility influences the tapasin dependence of two differentially disease-associated MHC Class I proteins",
abstract = "The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide-binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype.",
keywords = "Ankylosing spondylitis, HLA-B27, Major histocompatibility complex, Molecular dynamics, Natively unstructured proteins, Protein folding, Simulations",
author = "Abualrous, {Esam T.} and Susanne Fritzsche and Zeynep Hein and Al-Balushi, {Mohammed S.} and Peter Reinink and Boyle, {Louise H.} and Ursula Wellbrock and Antoniou, {Antony N.} and Sebastian Springer",
year = "2015",
month = "4",
day = "1",
doi = "10.1002/eji.201445307",
language = "English",
volume = "45",
pages = "1248--1257",
journal = "European Journal of Immunology",
issn = "0014-2980",
publisher = "Wiley-VCH Verlag",
number = "4",

}

TY - JOUR

T1 - F pocket flexibility influences the tapasin dependence of two differentially disease-associated MHC Class I proteins

AU - Abualrous, Esam T.

AU - Fritzsche, Susanne

AU - Hein, Zeynep

AU - Al-Balushi, Mohammed S.

AU - Reinink, Peter

AU - Boyle, Louise H.

AU - Wellbrock, Ursula

AU - Antoniou, Antony N.

AU - Springer, Sebastian

PY - 2015/4/1

Y1 - 2015/4/1

N2 - The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide-binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype.

AB - The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide-binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype.

KW - Ankylosing spondylitis

KW - HLA-B27

KW - Major histocompatibility complex

KW - Molecular dynamics

KW - Natively unstructured proteins

KW - Protein folding

KW - Simulations

UR - http://www.scopus.com/inward/record.url?scp=84927067945&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927067945&partnerID=8YFLogxK

U2 - 10.1002/eji.201445307

DO - 10.1002/eji.201445307

M3 - Article

VL - 45

SP - 1248

EP - 1257

JO - European Journal of Immunology

JF - European Journal of Immunology

SN - 0014-2980

IS - 4

ER -