Differential Transmembrane Domain GXXXG Motif Pairing Impacts Major Histocompatibility Complex (MHC) Class II Structure

Abstract

Background: Major histocompatibility complex class II molecules are structurally and functionally heterogeneous. Results: Combined mutagenesis and structural studies establish a role for pairing between conserved transmembrane (TM) GXXXG dimerization motifs in determining class II conformation. Conclusion: Differential pairing of highly conserved TM domain dimerization motifs contributes to class II structure and function. Significance: Global conformation contributes to the function of peptide-class II complexes.

A triad of molecular regions contribute to the formation of two distinct MHC class II conformers

“…More recently, we extended the initial structural studies of King and Dixon (King and Dixon, 2010) and identified two I-A k class II conformers that differ in pairing of transmembrane (TM) domain GxxxG dimerization motifs [Figure 1, (Dixon et al, 2014)]. Moreover, we have demonstrated that while M1 paired class II molecules numerically represent ~10% of cell surface class II, they can carry greater than 90% of MHC class II function (Barroso et al, 2015; Busman-Sahay et al, 2011; Sprent et al, 1981).…”

“…The 11-5.2 anti-I-A k monoclonal antibody (mAb) is distinctive in that it binds an epitope uniquely expressed on the extracellular domain of M1 paired I-A k class II molecules (Busman-Sahay et al, 2011; Dixon et al, 2014). While initial characterization of the 11-5.2 mAb suggested that it uniquely recognizes I-A k class II molecules and is thus specific for the private epitope of I-A k designated Ia.2 (Oi et al, 1978), subsequent study revealed low level binding to I-A r expressing cells, suggesting that it might be specific for the Ia.19 epitope that is shared between I-A k and I-A r (Devaux et al, 1984).…”

Antigen-B Cell Receptor Complexes Associate with Intracellular major histocompatibility complex (MHC) Class II Molecules

“…A Unique Role for M1-paired MHC Class II in BCR-mediated Antigen Processing and Presentation-Recently, we established that MHC class II molecules exist in two conformational states on the basis of alternative pairing of transmembrane domain GXXXG dimerization motifs (8,10,24) (Fig. 7A).…”

“…In contrast, ϳ10% of class II molecules exist as an M1-paired conformer that is marked by the presence of the Ia.2 epitope recognized by the 11-5.2 anti-I-A k mAb. This Ia.2 ϩ M1-paired I-A k class II conformer is highly effective at driving T cell stimulation, is enriched in lipid rafts, and has the ability to drive intracellular calcium signaling in B cells (8,10).…”

Microdomains, Inflammation, and Atherosclerosis

“…Given the importance of microdomains, also called nanodomains, in providing a platform for organizing the signaling of many receptors and proteins including the B cell receptor, T cell receptor 92–94 and major histocompatibility class receptors 95, 96 it follows that lipid raft composition must be carefully regulated. The cholesterol needed for lipid raft formation and maintenance can be derived from exogenous sources such as lipoproteins, especially LDL, or from cellular synthesis via the mevalonate pathway in the ER followed by transport to the plasma membrane.…”