Curvature and Hydrophobic forces drive oligomerization and modulate activity of rhodopsin in membranes

Ana Vitória Botelho, Thomas Huber, Thomas P. Sakmar, Michael F Brown

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

G protein-coupled receptors (GPCRs) are essential components of cellular signaling pathways. They are the targets of many current pharmaceuticals and are postulated to dimerize or oligomerize in cellular membranes in conjunction with their functional mechanisms. We demonstrate using fluorescence resonance energy transfer how association of rhodopsin occurs by long-range lipid-protein interactions due to geometrical forces, yielding greater receptor crowding. Constitutive association of rhodopsin is promoted by a reduction in membrane thickness (hydrophobic mismatch), but also by an increase in protein/lipid molar ratio, showing the importance of interactions extending well beyond a single annulus of boundary lipids. The fluorescence data correlate with the pK a for the MI-to-MII transition of rhodopsin, where deprotonation of the retinylidene Schiff base occurs in conjunction with helical movements leading to activation of the photoreceptor. A more dispersed membrane environment optimizes formation of the MII conformation that results in visual function. A flexible surface model explains both the dispersal and activation of rhodopsin in terms of bilayer curvature deformation (strain) and hydrophobic solvation energy. The bilayer stress is related to the lateral pressure profile in terms of the spontaneous curvature and associated bending rigidity. Transduction of the strain energy (frustration) of the bilayer drives protein oligomerization and conformational changes in a coupled manner. Our findings illuminate the physical principles of membrane protein association due to chemically nonspecific interactions in fluid lipid bilayers. Moreover, they yield a conceptual framework for understanding how the tightly regulated lipid compositions of cellular membranes influence their protein-mediated functions.

Original languageEnglish (US)
Pages (from-to)4464-4477
Number of pages14
JournalBiophysical Journal
Volume91
Issue number12
DOIs
StatePublished - Dec 2006

Fingerprint

Rhodopsin
Lipids
Membranes
Proteins
Fluorescence Resonance Energy Transfer
Crowding
Frustration
Schiff Bases
Lipid Bilayers
G-Protein-Coupled Receptors
Membrane Proteins
Fluorescence
Pressure
Drive
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biophysics

Cite this

Curvature and Hydrophobic forces drive oligomerization and modulate activity of rhodopsin in membranes. / Botelho, Ana Vitória; Huber, Thomas; Sakmar, Thomas P.; Brown, Michael F.

In: Biophysical Journal, Vol. 91, No. 12, 12.2006, p. 4464-4477.

Research output: Contribution to journalArticle

Botelho, Ana Vitória ; Huber, Thomas ; Sakmar, Thomas P. ; Brown, Michael F. / Curvature and Hydrophobic forces drive oligomerization and modulate activity of rhodopsin in membranes. In: Biophysical Journal. 2006 ; Vol. 91, No. 12. pp. 4464-4477.
@article{467e173c722541a1931b54f016fdd17b,
title = "Curvature and Hydrophobic forces drive oligomerization and modulate activity of rhodopsin in membranes",
abstract = "G protein-coupled receptors (GPCRs) are essential components of cellular signaling pathways. They are the targets of many current pharmaceuticals and are postulated to dimerize or oligomerize in cellular membranes in conjunction with their functional mechanisms. We demonstrate using fluorescence resonance energy transfer how association of rhodopsin occurs by long-range lipid-protein interactions due to geometrical forces, yielding greater receptor crowding. Constitutive association of rhodopsin is promoted by a reduction in membrane thickness (hydrophobic mismatch), but also by an increase in protein/lipid molar ratio, showing the importance of interactions extending well beyond a single annulus of boundary lipids. The fluorescence data correlate with the pK a for the MI-to-MII transition of rhodopsin, where deprotonation of the retinylidene Schiff base occurs in conjunction with helical movements leading to activation of the photoreceptor. A more dispersed membrane environment optimizes formation of the MII conformation that results in visual function. A flexible surface model explains both the dispersal and activation of rhodopsin in terms of bilayer curvature deformation (strain) and hydrophobic solvation energy. The bilayer stress is related to the lateral pressure profile in terms of the spontaneous curvature and associated bending rigidity. Transduction of the strain energy (frustration) of the bilayer drives protein oligomerization and conformational changes in a coupled manner. Our findings illuminate the physical principles of membrane protein association due to chemically nonspecific interactions in fluid lipid bilayers. Moreover, they yield a conceptual framework for understanding how the tightly regulated lipid compositions of cellular membranes influence their protein-mediated functions.",
author = "Botelho, {Ana Vit{\'o}ria} and Thomas Huber and Sakmar, {Thomas P.} and Brown, {Michael F}",
year = "2006",
month = "12",
doi = "10.1529/biophysj.106.082776",
language = "English (US)",
volume = "91",
pages = "4464--4477",
journal = "Biophysical Journal",
issn = "0006-3495",
publisher = "Biophysical Society",
number = "12",

}

TY - JOUR

T1 - Curvature and Hydrophobic forces drive oligomerization and modulate activity of rhodopsin in membranes

AU - Botelho, Ana Vitória

AU - Huber, Thomas

AU - Sakmar, Thomas P.

AU - Brown, Michael F

PY - 2006/12

Y1 - 2006/12

N2 - G protein-coupled receptors (GPCRs) are essential components of cellular signaling pathways. They are the targets of many current pharmaceuticals and are postulated to dimerize or oligomerize in cellular membranes in conjunction with their functional mechanisms. We demonstrate using fluorescence resonance energy transfer how association of rhodopsin occurs by long-range lipid-protein interactions due to geometrical forces, yielding greater receptor crowding. Constitutive association of rhodopsin is promoted by a reduction in membrane thickness (hydrophobic mismatch), but also by an increase in protein/lipid molar ratio, showing the importance of interactions extending well beyond a single annulus of boundary lipids. The fluorescence data correlate with the pK a for the MI-to-MII transition of rhodopsin, where deprotonation of the retinylidene Schiff base occurs in conjunction with helical movements leading to activation of the photoreceptor. A more dispersed membrane environment optimizes formation of the MII conformation that results in visual function. A flexible surface model explains both the dispersal and activation of rhodopsin in terms of bilayer curvature deformation (strain) and hydrophobic solvation energy. The bilayer stress is related to the lateral pressure profile in terms of the spontaneous curvature and associated bending rigidity. Transduction of the strain energy (frustration) of the bilayer drives protein oligomerization and conformational changes in a coupled manner. Our findings illuminate the physical principles of membrane protein association due to chemically nonspecific interactions in fluid lipid bilayers. Moreover, they yield a conceptual framework for understanding how the tightly regulated lipid compositions of cellular membranes influence their protein-mediated functions.

AB - G protein-coupled receptors (GPCRs) are essential components of cellular signaling pathways. They are the targets of many current pharmaceuticals and are postulated to dimerize or oligomerize in cellular membranes in conjunction with their functional mechanisms. We demonstrate using fluorescence resonance energy transfer how association of rhodopsin occurs by long-range lipid-protein interactions due to geometrical forces, yielding greater receptor crowding. Constitutive association of rhodopsin is promoted by a reduction in membrane thickness (hydrophobic mismatch), but also by an increase in protein/lipid molar ratio, showing the importance of interactions extending well beyond a single annulus of boundary lipids. The fluorescence data correlate with the pK a for the MI-to-MII transition of rhodopsin, where deprotonation of the retinylidene Schiff base occurs in conjunction with helical movements leading to activation of the photoreceptor. A more dispersed membrane environment optimizes formation of the MII conformation that results in visual function. A flexible surface model explains both the dispersal and activation of rhodopsin in terms of bilayer curvature deformation (strain) and hydrophobic solvation energy. The bilayer stress is related to the lateral pressure profile in terms of the spontaneous curvature and associated bending rigidity. Transduction of the strain energy (frustration) of the bilayer drives protein oligomerization and conformational changes in a coupled manner. Our findings illuminate the physical principles of membrane protein association due to chemically nonspecific interactions in fluid lipid bilayers. Moreover, they yield a conceptual framework for understanding how the tightly regulated lipid compositions of cellular membranes influence their protein-mediated functions.

UR - http://www.scopus.com/inward/record.url?scp=33845505655&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845505655&partnerID=8YFLogxK

U2 - 10.1529/biophysj.106.082776

DO - 10.1529/biophysj.106.082776

M3 - Article

C2 - 17012328

AN - SCOPUS:33845505655

VL - 91

SP - 4464

EP - 4477

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 12

ER -