Structure of the Ebola Virus Envelope Protein MPER/TM Domain and its Interaction with the Fusion Loop Explains their Fusion Activity

Lee, Jun Young; Nyenhuis, David A.; Nelson, Elizabeth A.; Cafiso, David S.; White, Judith M.; Tamm, Lukas K.

doi:10.1016/j.bpj.2016.11.468

Cited by 15 publications

(24 citation statements)

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“…In addition, some viral fusion proteins contain segments that may interact directly with cholesterol. This includes the membrane proximal region of the GP2 protein of Ebola virus that contains the sequence GXXGXXXA, suggested to interact with cholesterol [99]. The sequence GXXXG is often associated with protein dimerization, but this and similar sequences have been shown to also interact with cholesterol in the amyloid precursor protein [100].…”

Section: Role Of Cholesterol In Membrane Fusionmentioning

confidence: 99%

Cholesterol-Recognition Motifs in Membrane Proteins

Fantini

Epand

Barrantes

2019

Advances in Experimental Medicine and Biology

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The impact of cholesterol on the structure and function of membrane proteins was recognized several decades ago, but the molecular mechanisms underlying these effects have remained elusive. There appear to be multiple mechanisms by which cholesterol interacts with proteins. A complete understanding of these motifs is still undergoing refinement. Initially, cholesterol was thought to exert only non-specific effects on membrane fluidity. It was later shown that this lipid could specifically interact with membrane proteins and affect both their structure and function. In this article, we have summarized and critically analyzed our evolving understanding of the affinity, specificity and stereoselectivity of the interactions of cholesterol with membrane proteins. We review the different computational approaches that are currently used to identify cholesterol binding sites in membrane proteins and the biochemical logic that governs each type of site, including CRAC, CARC, SSD and amphipathic helix motifs. There are physiological implications of these cholesterolrecognition motifs for G-protein coupled receptors (GPCR) and ion channels, in membrane trafficking and membrane fusion (SNARE) proteins. There are also pathological implications of cholesterol binding to proteins involved in neurological disorders (Alzheimer, Parkinson, Creutzfeldt-Jakob) and HIV fusion. In each case, our discussion is focused on the key molecular aspects of the cholesterol and amino acid motifs in membrane-embedded regions of membrane proteins that define the physiologically relevant crosstalk between the two. Our understanding of the factors that determine if these motifs are functional in cholesterol binding will allow us enhanced predictive ability.

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Section: Role Of Cholesterol In Membrane Fusionmentioning

confidence: 99%

Cholesterol-Recognition Motifs in Membrane Proteins

Fantini

Epand

Barrantes

2019

Advances in Experimental Medicine and Biology

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“…Cholesterol has a small hydrophilic head group and a bulky steroid backbone, and is a vital component of biological membranes. Accumulating evidence supports the importance of cholesterol in various fusion events, such as exocytosis (Wasser et al, 2007;Linetti et al, 2010) and viral fusion (Klug et al, 2017;Lee et al, 2017). Cholesterol is thought to participate in membrane fusion mainly by altering the biophysical properties of the membrane, such as the fluidity, thickness, curvature, and stability of lipid bilayers (Yang et al, 2016).…”

Section: Cholesterol and Atlastin-mediated Fusionmentioning

confidence: 99%

The Effects of Regulatory Lipids on Intracellular Membrane Fusion Mediated by Dynamin-Like GTPases

Moon

Jun

2020

Front. Cell Dev. Biol.

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Membrane fusion mediates a number of fundamental biological processes such as intracellular membrane trafficking, fertilization, and viral infection. Biological membranes are composed of lipids and proteins; while lipids generally play a structural role, proteins mediate specific functions in the membrane. Likewise, although proteins are key players in the fusion of biological membranes, there is emerging evidence supporting a functional role of lipids in various membrane fusion events. Intracellular membrane fusion is mediated by two protein families: SNAREs and membrane-bound GTPases. SNARE proteins are involved in membrane fusion between transport vesicles and their target compartments, as well as in homotypic fusion between organelles of the same type. Membrane-bound GTPases mediate mitochondrial fusion and homotypic endoplasmic reticulum fusion. Certain membrane lipids, known as regulatory lipids, regulate these membrane fusion events by directly affecting the function of membranebound GTPases, instead of simply changing the biophysical and biochemical properties of lipid bilayers. In this review, we provide a summary of the current understanding of how regulatory lipids affect GTPase-mediated intracellular membrane fusion by focusing on the functions of regulatory lipids that directly affect fusogenic GTPases.

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“…Samples were loaded into quartz capillaries of 1.5 ID x 1.8 OD 100 mm length and flash frozen in liquid nitrogen then run at 80 K. DEER data were collected using a dead-time free four-pulse sequence with 16-step phase cycling (one 16 ns π/2 and two 32 ns π observe pulses separated by a 32 ns π pump pulse). (38,39) Pump and observe pulses were separated by 75 MHz. DeerAnalysis2015 or DD was used for the removal of the dipolar background from the raw DEER data, V(t)/V(0) (39-42), and Tikhonov regularization was used to extract distance distributions from the resulting form factors, F(t)/F(0) (38,43).…”

Section: Continuous Wave Eprmentioning

confidence: 99%

“…(38,39) Pump and observe pulses were separated by 75 MHz. DeerAnalysis2015 or DD was used for the removal of the dipolar background from the raw DEER data, V(t)/V(0) (39-42), and Tikhonov regularization was used to extract distance distributions from the resulting form factors, F(t)/F(0) (38,43).…”

Section: Continuous Wave Eprmentioning

confidence: 99%

Phosphatidylinositol 4,5 bisphosphate controls the cis and trans interactions of synaptotagmin 1

Nyenhuis

Thapa

Cafiso

2019

Preprint

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Synaptotagmin 1 acts as the Ca 2+ -sensor for synchronous neurotransmitter release; however, the mechanism by which it functions is not understood and is presently a topic of considerable interest. Here we describe measurements on full-length membrane reconstituted synaptotagmin 1 using site-directed spin labeling where we characterize the linker region as well as the cis (vesicle membrane) and trans (cytoplasmic membrane) binding of its two C2 domains. In the full-length protein, the C2A domain does not undergo membrane insertion in the absence of Ca 2+ ; however, the C2B domain will bind to and penetrate in trans to a membrane containing phosphatidylinositol 4,5 bisphosphate (PIP 2 ), even if phosphatidylserine (PS) is present in the cis membrane. In the presence of Ca 2+ , the Ca 2+ -binding loops of C2A and C2B both insert into the membrane interface; moreover, C2A preferentially inserts into PS containing bilayers and will bind in a cis configuration to membranes containing PS even if a PIP 2 membrane is presented in trans. The data are consistent with a bridging activity for Syt1 where the two domains bind to opposing vesicle and plasma membranes. The failure of C2A to bind membranes in the absence of Ca 2+ and the long unstructured segment linking C2A to the vesicle membrane indicates that synaptotagmin 1 could act to significantly shorten the vesicle-plasma membrane distance with increasing levels of Ca 2+ .

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Structure of the Ebola Virus Envelope Protein MPER/TM Domain and its Interaction with the Fusion Loop Explains their Fusion Activity

Cited by 15 publications

References 0 publications

Cholesterol-Recognition Motifs in Membrane Proteins

Cholesterol-Recognition Motifs in Membrane Proteins

The Effects of Regulatory Lipids on Intracellular Membrane Fusion Mediated by Dynamin-Like GTPases

Phosphatidylinositol 4,5 bisphosphate controls the cis and trans interactions of synaptotagmin 1

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