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. Also watch the Video Abstract.
authors.affiliation: Department of Life Science and Chemistry, Jacobs University Bremen, Bremen, Germany; Department of Physics, Faculty of Science, Ain Shams University, Cairo, Egypt.
authors.forename: Esam T
authors.initials: ET
authors.lastname: Abualrous
authors.forename: Susanne
authors.initials: S
authors.lastname: Fritzsche
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Hein
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Al-Balushi
authors.forename: Peter
authors.initials: P
authors.lastname: Reinink
authors.forename: Louise H
authors.initials: LH
authors.lastname: Boyle
authors.forename: Ursula
authors.initials: U
authors.lastname: Wellbrock
authors.forename: Antony N
authors.initials: AN
authors.lastname: Antoniou
authors.forename: Sebastian
authors.initials: S
authors.lastname: Springer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017422:Sequence Analysis, DNA; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000276:immunology*
chemical_list: C464936:HLA-B*27:05 antigen; C464937:HLA-B*27:09 antigen; D015796:HLA-B27 Antigen; D026901:Membrane Transport Proteins; D018832:Molecular Chaperones; C107762:tapasin
keywords: Ankylosing spondylitis; HLA-B27; Major histocompatibility complex; Molecular dynamics; Natively unstructured proteins; Protein folding; Simulations