Alpha-helical transmembrane (TM) proteins possess a characteristic hydrophobic length that is determined by the number of hydrophobic residues in their membrane-spanning alpha helices. Theoretical and experimental studies using model peptides and bilayers suggest that hydrophobic mismatch can drive the association of membrane proteins. However, the possibility that hydrophobic mismatch drives self-association of TM proteins has not been tested in living cells. Hydrophobic mismatch might also be important for oligomerization of G protein-coupled receptors (GPCRs), the largest family of cell surface receptors. The first objective of the proposed project is to test the general hypothesis that hydrophobic mismatch can serve as a mechanism that drives TM protein association in living cells. We will test this hypothesis by studying self-association of engineered single-TM proteins with variable hydrophobic lengths. The second objective of the proposed project is to test the specific hypothesis that hydrophobic mismatch contributes to self-association of GPCRs in the plasma membrane of living cells. We will test this hypothesis using self-association of ?2-adrenoreceptors (?2ARs) in HEK 293 cells as a model. If successful these experiments will help to define the mechanisms of TM protein organization in live cells, the structural basis of ?2AR self-association, and may provide tools to study the function of monomeric ?2ARs in living cells.

Public Health Relevance

G protein-coupled receptors are the targets of more prescribed drugs than any other class of receptor. The realization that GPCRs can assemble as dimers or higher-order oligomers suggests the possibility that these complexes might have unique pharmacological properties, thus greatly expanding the number of potential therapeutic targets. In order to fully evaluate this possibility it is necessary to understand both the mechanism of GPCR self-assembly and the impact of self-assembly on function. The goal of proposed research is to determine the mechanism of self-assembly, which in turn may provide the tools needed to determine the functional impact of self-assembly.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-A (04))
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Chin, Jean
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Georgia Regents University
Schools of Medicine
United States
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Gavalas, Anthony; Lan, Tien-Hung; Liu, Qiuju et al. (2013) Segregation of family A G protein-coupled receptor protomers in the plasma membrane. Mol Pharmacol 84:346-52
Li, Chunman; Fan, Yi; Lan, Tien-Hung et al. (2012) Rab26 modulates the cell surface transport of ?2-adrenergic receptors from the Golgi. J Biol Chem 287:42784-94
Lan, Tien-Hung; Liu, Qiuju; Li, Chunman et al. (2012) Sensitive and high resolution localization and tracking of membrane proteins in live cells with BRET. Traffic 13:1450-6
Dong, Chunmin; Nichols, Charles D; Guo, Jianhui et al. (2012) A triple arg motif mediates ?(2B)-adrenergic receptor interaction with Sec24C/D and export. Traffic 13:857-68
Lan, Tien-Hung; Kuravi, Sudhakiranmayi; Lambert, Nevin A (2011) Internalization dissociates ?2-adrenergic receptors. PLoS One 6:e17361
Urizar, Eneko; Yano, Hideaki; Kolster, Rachel et al. (2011) CODA-RET reveals functional selectivity as a result of GPCR heteromerization. Nat Chem Biol 7:624-30
Johnston, Jennifer M; Aburi, Mahalaxmi; Provasi, Davide et al. (2011) Making structural sense of dimerization interfaces of delta opioid receptor homodimers. Biochemistry 50:1682-90
Qin, Kou; Dong, Chunmin; Wu, Guangyu et al. (2011) Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers. Nat Chem Biol 7:740-7