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 language | English |
|---|---|
| Pages (from-to) | 1248-1257 |
| Number of pages | 10 |
| Journal | European Journal of Immunology |
| Volume | 45 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 1 2015 |
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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 journal › Article
}
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
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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 -