King, G. (Gavin) and Dixon, Ann M.. (2010) Evidence for role of transmembrane helix-helix interactions in the assembly of the Class II major histocompatibility complex. Molecular BioSystems, Vol.6 (No.9). pp. 1650-1661. ISSN 1742-206X

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Abstract

The Major Histocompatibility Complex Class II (Class II MHC) and invariant chain (Ii) proteins are key initiators of an immune response to invading pathogens. Following biosynthesis, three MHC alpha/beta hetero-dimers associate with an Ii homotrimer to form a nine-chain protein complex. Only as part of this complex are the MHC molecules exported to the cell surface to trigger an immune response. Previous reports implicate the transmembrane (TM) domains of all three proteins in correct assembly, ligand binding and function of Class II MHC. Building on our previous work that revealed the Ii TM domain may contribute significantly to correct assembly of the full-length protein, we have used a variety of genetic, biophysical and computational methods to investigate the role of the TM domains in stabilizing MHC alpha/beta heterodimers. Using the in vivo GALLEX assay, we find that the TM domains of both proteins form strong homo-and hetero-oligomers in natural membranes that are stabilized by GXXXG motifs within the sequence. Forster resonance energy transfer (FRET) measurements, using fluorescently-tagged peptides derived from the TM domains of each protein, were then employed to confirm the presence of TM helix-helix hetero-interactions in detergent micelles, as well as the stoichiometry of these interactions. Our results are summarized in a revised model of Class II MHC-Ii complex formation that illustrates key protein-protein contacts. This work provides the first evidence that the TM domains of the Class II MHC molecules are capable of significant protein-protein interactions that may help to stabilize or even initiate formation of the MHC-Ii complex.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology Q Science > QR Microbiology
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Major histocompatibility complex, Protein-protein interactions
Journal or Publication Title:	Molecular BioSystems
Publisher:	Royal Society of Chemistry
ISSN:	1742-206X
Official Date:	September 2010
Volume:	Vol.6
Number:	No.9
Number of Pages:	12
Page Range:	pp. 1650-1661
Identification Number:	10.1039/c002241a
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Medical Research Council (Great Britain) (MRC)
Grant number:	G0601114 (MRC)
URI:	http://wrap.warwick.ac.uk/id/eprint/5363

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