Molecular recognition of a single sphingolipid species by a protein’s transmembrane domain

Contreras, F.‐Xabier; Ernst, Andreas; Haberkant, Per; Björkholm, Patrik; Lindahl, Erik; Gönen, Başak; Tischer, Christian; Elofsson, Arne; Heijne, Gunnar von; Thiele, Christoph; Pepperkok, Rainer; Wieland, Felix; Brügger, Britta

doi:10.1038/nature10742

Cited by 349 publications

(342 citation statements)

References 22 publications

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“…One model proposes that some proteins serve as nucleation sites for raft domains by organizing ' shells ' of raft lipids around their membrane spans (Anderson and Jacobson , 2002 ;Sharpe et al , 2010 ). Recent identification of a conserved sphingolipid-binding signature in a variety of membrane proteins (Contreras et al , 2012 ) is consistent with the idea that specific lipids may influence the lateral organization of proteins and vice versa. In addition, there is evidence that electrostatic proteinlipid interactions can generate membrane microdomains enriched in phosphoinositide-4,5-bisphosphate (PIP 2 ) and the SNAP-receptor syntaxin-A1 ( Figure 1C).…”

Section: Microcompartments Within Membranessupporting

confidence: 52%

Cellular microcompartments constitute general suborganellar functional units in cells

Holthuis

Ungermann

2013

Biological Chemistry

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All cells are compartmentalized to facilitate enzymatic reactions or cellular dynamics. In eukaryotic cells, organelles differ in their protein/lipid repertoire, luminal ion composition, pH, and redox status. In addition, organelles contain specialized subcompartments even within the same membrane or within its lumen. Moreover, the bacterial plasma membrane reveals a remarkable degree of organization, which is recapitulated in eukaryotic cells and often linked to cell signaling. Finally, protein-based compartments are also known in the bacterial and eukaryotic cytosol. As the organizing principle of such cellular subcompartments is likely similar, previous definitions like rafts, microdomains, and all kinds of ' -somes ' fall short as a general denominator to describe such suborganellar structures. Within this review, we will introduce the term cellular microcompartment as a general suborganellar functional unit and discuss its relevance to understand subcellular organization and function.

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Section: Microcompartments Within Membranessupporting

confidence: 52%

Cellular microcompartments constitute general suborganellar functional units in cells

Holthuis

Ungermann

2013

Biological Chemistry

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“…FLAG-tagged GP 2 and GP 1,2 constructs and variants thereof and ASGR1, as a negative control, were probed for protein-cholesterol interaction in vivo. For this purpose, photoactivatable cholesterol was employed for photolabelling experiments as previously described 66 . In brief, HeLa cells were grown in six-well dishes and transfected using FuGENE HD (1 mg DNA þ 3 ml transfection reagent in 100 ml Opti-MEM (Invitrogen) at B60% confluency.…”

Section: Treatment Of Cells With Mbcd and Cbmentioning

confidence: 99%

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

et al. 2015

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The high pathogenicity of the Ebola virus reflects multiple concurrent processes on infection. Among other important determinants, Ebola fusogenic glycoprotein (GP) has been associated with the detachment of infected cells and eventually leads to vascular leakage and haemorrhagic fever. Here we report that the membrane-anchored GP is sufficient to induce the detachment of adherent cells. The results show that the detachment induced through either full-length GP 1,2 or the subunit GP 2 depends on cholesterol and the structure of the transmembrane domain. These data reveal a novel molecular mechanism in which GP regulates Ebola virus assembly and suggest that cholesterol-reducing agents could be useful as therapeutics to counteract GP-mediated cell detachment.

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“…These proteins include soluble transporters (e.g., CERT), the S1P GPCRs, and p24, a membrane protein that participates in COPI vesicle formation (Contreras et al 2012). Recent crystallographic studies have illuminated the molecular interactions that enable specific recognition of sphingolipids, revealing hydrophobic binding pockets that can discriminate features such as headgroup structure and acyl chain length (Malinina et al 2004(Malinina et al , 2006Kudo et al 2008;Contreras et al 2012;Hanson et al 2012). Although the above proteins are not known to be homeostatic sensors, such sensors may use similar modes of molecular recognition.…”

Section: Sphingolipid Homeostasis In the Er And Beyondmentioning

confidence: 99%

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Breslow

2013

Cold Spring Harbor Perspectives in Biology

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Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids-from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease.

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Molecular recognition of a single sphingolipid species by a protein’s transmembrane domain

Cited by 349 publications

References 22 publications

Cellular microcompartments constitute general suborganellar functional units in cells

Cellular microcompartments constitute general suborganellar functional units in cells

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

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