Skip to main content
Article thumbnail
Location of Repository

Investigating helix-helix interactions in the transmembrane domains of membrane proteins

By Gavin W. King


Helix-helix interactions between membrane-spanning transmembrane (TM)\ud domains have been shown to drive the assembly of α-helical membrane proteins\ud within biological membranes. However, the rules that determine these interactions\ud are not yet fully understood, despite such interactions being found in an increasing\ud number of proteins. Recent work has implicated TM domain interactions in the\ud formation of the protein complex Ii-MHC, formed from the association of Major\ud Histocompatibility Complex Class II (MHC) and the MHC-associated-Invariant\ud Chain (Ii) proteins. Following biosynthesis, three MHC α/βheterodimers bind to\ud the Ii homotrimer to form a nonameric Ii-MHC complex within the endoplasmic\ud reticulum. This is a critical step in the export of MHC molecules to the antigen\ud presentation system and hence the activation of an immune response to a\ud pathogen. In this study we have explored the TM domain interactions within the\ud Ii-MHC complex. Results from in vivo and in vitro experiments revealed the TM\ud domains of the α- and β-chains of MHC have a propensity to self-associate into\ud homo-dimers and to associate with one another to form hetero-dimers. Highly\ud conserved GxxxG motifs (known to drive dimerization) were implicated in these\ud interactions. The TM domain of Ii was confirmed to self-associate to form trimers\ud by in vivo and in vitro methods, but surprisingly also displayed additional\ud oligomeric states suggesting the interaction is not as specific as was previously\ud thought. Furthermore, we show that in vivo, the TM domain of Ii can associate\ud with those of the α- and β-chains of MHC, whilst in vitro methods suggested Ii\ud preferentially binds to α-chains. Collectively, these findings strongly suggest that\ud the TM domains of Ii and MHC have a role to play in the assembly of the Ii-MHC\ud complex, and hence the very important process of antigen presentation.\ud Additionally, in this study we have undertaken development of NMR\ud spectroscopy methods that have the potential to increase our understanding of not\ud only the Ii-MHC complex, but protein-protein interactions in general

Topics: QP
OAI identifier:

Suggested articles


  1. (2005). Forster resonance energy transfer in liposomes: measurements of transmembrane helix dimerization in the native bilayer environment." doi
  2. (2006). How hydrogen bonds shape membrane protein structure." Peptide Solvation and H-Bonds 72: doi
  3. (2001). How membranes shape protein structure." doi
  4. (2002). Ligand-independent dimer formation of epidermal growth factor receptor (EGFR) is a step separable from ligandinduced EGFR signaling." doi
  5. (1999). Membrane protein folding and stability: physical principles." doi
  6. (1990). Method of oriented circular dichroism." doi
  7. (2003). MHC class II-associated invariant chain isoforms regulate pulmonary immune responses." doi
  8. (2001). Polar residues drive association of polyleucine transmembrane helices." doi
  9. (2007). Probing the structure of the Ff bacteriophage major coat protein transmembrane helix dimer by solution NMR." doi
  10. (2003). Protein alignment by a coexpressed lanthanide-binding tag for the measurement of residual dipolar couplings." doi
  11. (2004). The exogenous pathway for antigen presentation on major histocompatibility complex class II and CD1 molecules." doi
  12. (2003). Translocons, thermodynamics, and the folding of membrane proteins." doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.