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

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...

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Bibliographic Details
Published in:European journal of immunology 2015-04, Vol.45 (4), p.1248-1257
Main Authors: Abualrous, Esam T., Fritzsche, Susanne, Hein, Zeynep, Al‐Balushi, Mohammed S., Reinink, Peter, Boyle, Louise H., Wellbrock, Ursula, Antoniou, Antony N., Springer, Sebastian
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Animals
Ankylosing spondylitis
Base Sequence
Binding sites
Binding Sites - genetics
Cell Line
Crystal structure
Dependence
Histocompatibility antigen HLA
HLA-B27 Antigen - chemistry
HLA-B27 Antigen - genetics
HLA‐B27
Humans
Major histocompatibility complex
Membrane Transport Proteins - metabolism
Mice
Models, Molecular
Molecular Chaperones - metabolism
Molecular dynamics
Molecular Dynamics Simulation
Natively unstructured proteins
Peptides
Protein Binding
Protein Conformation
Protein Folding
Proteins
Sequence Analysis, DNA
Simulations
Spondylitis
Spondylitis, Ankylosing - genetics
Spondylitis, Ankylosing - immunology
Tapasin
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Summary: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. Also watch the Video
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.201445307