Cooperative Gating and Spatial Organization of Membrane Proteins through Elastic Interactions

Ursell, Tristan; Huang, Kerwyn Casey; Peterson, Eric; Phillips, Rob

doi:10.1371/journal.pcbi.0030081

Cited by 115 publications

(216 citation statements)

References 71 publications

(139 reference statements)

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“…This deformation thins the membrane by 36%, thus providing a shorter pathway for a hydrophilic headgroup to cross. The computed membrane distortion energy value for nhTMEM16 is 8-20 times higher than theoretical and experimental values for gramicidin (25,35) and rhodopsin (36) and about twice as high as values estimated for the membrane associated gating energy of the mechanosensitive channel of large conductance (MscL) (37,38). Because the leaflet-to-leaflet distance is still large (18.3Å), thinning is not likely the sole mechanism.…”

Section: Discussionmentioning

confidence: 65%

Atomistic insight into lipid translocation by a TMEM16 scramblase

Bethel

Grabe

2016

Proc. Natl. Acad. Sci. U.S.A.

105

159

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The transmembrane protein 16 (TMEM16) family of membrane proteins includes both lipid scramblases and ion channels involved in olfaction, nociception, and blood coagulation. The crystal structure of the fungal Nectria haematococca TMEM16 (nhTMEM16) scramblase suggested a putative mechanism of lipid transport, whereby polar and charged lipid headgroups move through the low-dielectric environment of the membrane by traversing a hydrophilic groove on the membrane-spanning surface of the protein. Here, we use computational methods to explore the membrane-protein interactions involved in lipid scrambling. Fast, continuum membrane-bending calculations reveal a global pattern of charged and hydrophobic surface residues that bends the membrane in a large-amplitude sinusoidal wave, resulting in bilayer thinning across the hydrophilic groove. Atomic simulations uncover two lipid headgroup-interaction sites flanking the groove. The cytoplasmic site nucleates headgroup-dipole stacking interactions that form a chain of lipid molecules that penetrate into the groove. In two instances, a cytoplasmic lipid interdigitates into this chain, crosses the bilayer, and enters the extracellular leaflet, and the reverse process happens twice as well. Continuum membrane-bending analysis carried out on homology models of mammalian homologs shows that these family members also bend the membrane-even those that lack scramblase activity. Sequence alignments show that the lipid-interaction sites are conserved in many family members but less so in those with reduced scrambling ability. Our analysis provides insight into how large-scale membrane bending and protein chemistry facilitate lipid permeation in the TMEM16 family, and we hypothesize that membrane interactions also affect ion permeation.TMEM16 | lipid scrambling | continuum membrane models | simulation | anoctamin T he compositional asymmetry between the leaflets of the plasma membrane influences the signaling properties of cells. Scramblases are a class of proteins that disrupt membrane asymmetry by facilitating the transfer of phospholipids from one leaflet to the other in an energy-independent manner. These transmembrane proteins play a role in events such as coagulation of the blood and cellular apoptosis by transporting phosphatidylserine (PS) from the inner leaflet to the outer leaflet of the plasma membrane (1). In particular, transmembrane protein 16 (TMEM16) family members have gained recent attention for their role in phospholipid scrambling in platelets and fungi. The TMEM16 family members have diverse functions. For example, TMEM16A and -B are calcium-activated chloride channels, TMEM16F is a nonspecific cation channel and scramblase, and the fungal Aspergillus fumigatus TMEM16 is another dual scramblase/ion channel (2-6).The structure of the Nectria haematococca TMEM16 (nhTMEM16) membrane protein revealed a possible mechanism for phospholipid conduction across the membrane (Fig. 1A) (7). The protein forms a dimer, and each subunit has a hydrophilic groove composed of polar...

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Section: Discussionmentioning

confidence: 65%

Atomistic insight into lipid translocation by a TMEM16 scramblase

Bethel

Grabe

2016

Proc. Natl. Acad. Sci. U.S.A.

105

159

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“…Bending of membranes creates a mechanism for long-range lateral force transmittance, even though the membrane itself is liquid. Consequences of this include the exotic stripe and hexagonal patterns of domains that form in phase-separated membranes 23,36,[44][45][46] as well as protein-protein interactions and possibly regulation 39,47,48 . An important corollary of these observations is that forcibly bending membranes necessarily imposes differential forces on structures in the membrane.…”

Section: Membrane Physical Chemistrymentioning

confidence: 99%

Molecular mechanisms in signal transduction at the membrane

Groves

Kuriyan

2010

Nat Struct Mol Biol

262

255

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Signal transduction originates at the membrane, where the clustering of signaling proteins is a key step in transmitting a message. Membranes are difficult to study, and their influence on signaling is still only understood at the most rudimentary level. Recent advances in the biophysics of membranes, surveyed in this review, have highlighted a variety of phenomena that are likely to influence signaling activity, such as local composition heterogeneities and long-range mechanical effects. We discuss recent mechanistic insights into three signaling systems-Ras activation, Ephrin signaling and the control of actin nucleation-where the active role of membrane components is now appreciated and for which experimentation on the membrane is required for further understanding.The influence of the membrane surface environment on the behavior of proteins that are localized to the vicinity of the membrane is still poorly understood. This contrasts starkly with our now quite sophisticated understanding of the structural and chemical aspects of the individual protein components 1 . This lack of knowledge is a natural consequence of the fact that membranes are difficult to study in vitro and that detailed quantitative information is difficult to obtain in vivo 2 . The relative inaccessibility of membranes to classical methods of study effectively cloaks their role in signaling biochemistry. We suggest that what is known about membranes in signal transduction is just a glimmer of a much larger story, with many key aspects of membrane function still hidden beneath the cloak.Cell signaling relies on modular domains that generate protein-protein interactions at the membrane 3,4 . Equally critical are domains that recognize specific phospholipids and are thereby responsive to changes in membrane composition 5 , as best exemplified by the family of protein kinase C (PKC) isozymes 6,7 . The PKC isozymes transduce signals arising from the hydrolysis of phospholipids in the membrane and have a protein kinase domain linked to C1 domains and a C2 domain (Fig. 1). The C1 domains bind to diacylglycerol (DAG), whereas the C2 domain binds to negatively charged lipids, such as phosphatidylinositol-4,5,-bisphosphate (PIP 2 ) and to Ca 2+ ions 6,7 . The activation of PKC involves priming by phosphorylation, followed by the recruitment of PKC to the membrane by PIP 2 , Ca 2+ and DAG 7,8 . One important principle that emerged from PKC studies is that the individual lipidbinding modules of PKC have insufficient affinity for their target lipids and so require that both PIP 2 and DAG be present for effective activation of the enzyme. This requirement for © 2010 Nature America, Inc. All rights reserved. Correspondence should be addressed to J.K. (kuriyan@berkeley.edu) or J.T.G. (Jtgroves@lbl.gov). COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Published as: Nat Struct Mol Biol. 2010 June ; 17(6): 659-665. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscriptmultiple targeting signals is ofte...

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“…Tension gating of MscL channels was demonstrated and characterized through isolation of channels in gigaseal patches and recording electrical current as a function of membrane tension induced while applying pressure to the pipette (3,4). A molecular mechanism of channel opening in response to tension has been proposed on the basis of atomic structures, electron paramagnetic resonance (EPR) spectroscopic studies and molecular modeling (5)(6)(7)(8).…”

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confidence: 99%

Mechanistic basis for low threshold mechanosensitivity in voltage-dependent K ⁺ channels

Schmidt

Mármol

MacKinnon

2012

Proc. Natl. Acad. Sci. U.S.A.

118

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Living cells respond to mechanical forces applied to their outer membrane through processes referred to as "mechanosensation". Faced with hypotonic shock, to circumvent cell lysis, bacteria open large solute-passing channels to reduce the osmotic pressure gradient. In the vascular beds of vertebrate animals blood flow is regulated directly through mechanical distention-induced opening of stretch-activated channels in smooth muscle cells. Touch sensation is thought to originate in mechanically sensitive ion channels in nerve endings, and hearing in mechanically sensitive ion channels located in specialized cells of the ear. While the ubiquity of mechanosensation in living cells is evident, the ion channels underlying the transduction events in vertebrate animals have remained elusive. Here we demonstrate through electrophysiological recordings that voltage-dependent K þ (Kv) channels exhibit exquisite sensitivity to small (physiologically relevant in magnitude) mechanical perturbations of the cell membrane. The demonstrated mechanosensitivity is quantitatively consistent with membrane tension acting on a late-opening transition through stabilization of a dilated pore. This effect causes a shift in the voltage range over which Kv channels open as well as an increase in the maximum open probability. This mechanically induced shift could allow Kv channels and perhaps other voltage-dependent ion channels to play a role in mechanosensation.T he only form of mechanosensation for which we have a good molecular understanding is that mediated by mechanosensitive channels in bacteria (1, 2). The mechanosensitive channel of large conductance (MscL) is a membrane-stretch-activated channel that opens when bacteria swell under hypotonic conditions, as occurs when it rains. Under high membrane tension MscL channels open wide enough to allow molecules up to a size of about 40 kDa to pass through their pore, relieving an osmotic pressure gradient that would otherwise lead to cell lysis and death. Tension gating of MscL channels was demonstrated and characterized through isolation of channels in gigaseal patches and recording electrical current as a function of membrane tension induced while applying pressure to the pipette (3, 4). A molecular mechanism of channel opening in response to tension has been proposed on the basis of atomic structures, electron paramagnetic resonance (EPR) spectroscopic studies and molecular modeling (5-8).Stretch activation of ion channels from eukaryotic cells, including Kv channels, has been studied using the same method of pipette pressurization (9, 10). Pressurization of a gigaseal patch has been shown in a number of cases to alter channel gating, however, the method has an important limitation. A gigaseal membrane patch is already under considerable baseline tension prior to the application of pressure. The baseline tension of the membrane in a gigaseal patch originates in the adherence of lipid to glass, which is the basis of an electrical gigaseal, and in magnitude is in the range of 0.5 to 4 mN...

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Cooperative Gating and Spatial Organization of Membrane Proteins through Elastic Interactions

Cited by 115 publications

References 71 publications

Atomistic insight into lipid translocation by a TMEM16 scramblase

Atomistic insight into lipid translocation by a TMEM16 scramblase

Molecular mechanisms in signal transduction at the membrane

Mechanistic basis for low threshold mechanosensitivity in voltage-dependent K ⁺ channels

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Cooperative Gating and Spatial Organization of Membrane Proteins through Elastic Interactions

Cited by 115 publications

References 71 publications

Atomistic insight into lipid translocation by a TMEM16 scramblase

Atomistic insight into lipid translocation by a TMEM16 scramblase

Molecular mechanisms in signal transduction at the membrane

Mechanistic basis for low threshold mechanosensitivity in voltage-dependent K + channels

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Mechanistic basis for low threshold mechanosensitivity in voltage-dependent K ⁺ channels