title: Differential transmembrane domain GXXXG motif pairing impacts major histocompatibility complex (MHC) class II structure.
abstract: Major histocompatibility complex (MHC) class II molecules exhibit conformational heterogeneity, which influences their ability to stimulate CD4 T cells and drive immune responses. Previous studies suggest a role for the transmembrane domain of the class II αβ heterodimer in determining molecular structure and function. Our previous studies identified an MHC class II conformer that is marked by the Ia.2 epitope. These Ia.2(+) class II conformers are lipid raft-associated and able to drive both tyrosine kinase signaling and efficient antigen presentation to CD4 T cells. Here, we establish that the Ia.2(+) I-A(k) conformer is formed early in the class II biosynthetic pathway and that differential pairing of highly conserved transmembrane domain GXXXG dimerization motifs is responsible for formation of Ia.2(+) versus Ia.2(-) I-A(k) class II conformers and controlling lipid raft partitioning. These findings provide a molecular explanation for the formation of two distinct MHC class II conformers that differ in their inherent ability to signal and drive robust T cell activation, providing new insight into the role of MHC class II in regulating antigen-presenting cell-T cell interactions critical to the initiation and control of multiple aspects of the immune response.
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Dixon
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208.
authors.forename: Lisa
authors.initials: L
authors.lastname: Drake
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208.
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Hughes
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sargent
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208.
authors.forename: Danielle
authors.initials: D
authors.lastname: Hunt
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Harton
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208. Electronic address: drakej@mail.amc.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Drake
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017386:Sequence Homology, Amino Acid
chemical_list: D000949:Histocompatibility Antigens Class II
keywords: Antigen Presentation; Lipid Raft; Major Histocompatibility Complex (MHC); Molecular Modeling; Protein Conformation