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. Also watch the Video Abstract.

• Authors: Esam T Abualrous, Susanne Fritzsche, Zeynep Hein, Mohammed S Al-Balushi, Peter Reinink, Louise H Boyle, Ursula Wellbrock, Antony N Antoniou, Sebastian Springer
• Journal: European journal of immunology (Eur J Immunol) Vol. 45 Issue 4 Pg. 1248-57 (Apr 2015) ISSN: 1521-4141 [Electronic] Germany
• PMID: 25615938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• HLA-B*27:05 antigen
• HLA-B*27:09 antigen
• HLA-B27 Antigen
• Membrane Transport Proteins
• Molecular Chaperones
• tapasin

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Binding Sites (genetics)
• Cell Line
• HLA-B27 Antigen (chemistry, genetics)
• Humans
• Membrane Transport Proteins (metabolism)
• Mice
• Models, Molecular
• Molecular Chaperones (metabolism)
• Molecular Dynamics Simulation
• Protein Binding
• Protein Conformation
• Protein Folding
• Sequence Analysis, DNA
• Spondylitis, Ankylosing (genetics, immunology)