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Cholesterol recognition motif

Matthew R Elkins, Jonathan K Williams, Martin D Gelenter, Peng Dai, Byungsu Kwon, Ivan V Sergeyev, Bradley L Pentelute, Mei Hong
The influenza M2 protein not only forms a proton channel but also mediates membrane scission in a cholesterol-dependent manner to cause virus budding and release. The atomic interaction of cholesterol with M2, as with most eukaryotic membrane proteins, has long been elusive. We have now determined the cholesterol-binding site of the M2 protein in phospholipid bilayers using solid-state NMR spectroscopy. Chain-fluorinated cholesterol was used to measure cholesterol proximity to M2 while sterol-deuterated cholesterol was used to measure bound-cholesterol orientation in lipid bilayers...
December 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
Ricardo J Ferreira, Cátia A Bonito, M Natália D S Cordeiro, Maria-José U Ferreira, Daniel J V A Dos Santos
Efflux pumps of the ATP-binding cassette transporters superfamily (ABC transporters) are frequently involved in the multidrug-resistance (MDR) phenomenon in cancer cells. Herein, we describe a new atomistic model for the MDR-related ABCG2 efflux pump, also named breast cancer resistance protein (BCRP), based on the recently published crystallographic structure of the ABCG5/G8 heterodimer sterol transporter, a member of the ABCG family involved in cholesterol homeostasis. By means of molecular dynamics simulations and molecular docking, a far-reaching characterization of the ABCG2 homodimer was obtained...
November 14, 2017: Scientific Reports
Song Tan, Peng Zhang, Wei Xiao, Bing Feng, Lan-You Chen, Shuang Li, Peng Li, Wei-Zhong Zhao, Xiao-Ting Qi, Li-Ping Yin
Iron is essential for most living organisms. The iron-regulated transporter1 (IRT1) plays a major role in iron uptake in roots, and its trafficking from endoplasmic reticulum (ER) to plasma membrane (PM) is tightly coordinated with changes in iron environment. However, studies on the IRT1 response are limited. Here, we report that Malus xiaojinesis IRT1 (MxIRT1) associates with detergent-resistant membranes (DRMs, a biochemical counterpart of PM microdomains), whereas the PM microdomains are known platforms for signal transduction in the PM...
February 2018: Traffic
Coralie Di Scala, Carlos J Baier, Luke S Evans, Philip T F Williamson, Jacques Fantini, Francisco J Barrantes
Cholesterol is a ubiquitous neutral lipid, which finely tunes the activity of a wide range of membrane proteins, including neurotransmitter and hormone receptors and ion channels. Given the scarcity of available X-ray crystallographic structures and the even fewer in which cholesterol sites have been directly visualized, application of in silico computational methods remains a valid alternative for the detection and thermodynamic characterization of cholesterol-specific sites in functionally important membrane proteins...
2017: Current Topics in Membranes
Jiri Masin, Jana Roderova, Adriana Osickova, Petr Novak, Ladislav Bumba, Radovan Fiser, Peter Sebo, Radim Osicka
The adenylate cyclase toxin-hemolysin (CyaA, ACT or AC-Hly) translocates its adenylate cyclase (AC) enzyme domain into target cells in a step that depends on membrane cholesterol content. We thus examined what role in toxin activities is played by the five putative cholesterol recognition amino acid consensus (CRAC) motifs predicted in CyaA hemolysin moiety. CRAC-disrupting phenylalanine substitutions had no impact on toxin activities and these were not inhibited by free cholesterol, showing that the putative CRAC motifs are not involved in cholesterol binding...
August 24, 2017: Scientific Reports
Pablo Carravilla, Antonio Cruz, Itziar Martin-Ugarte, Itziar R Oar-Arteta, Johanna Torralba, Beatriz Apellaniz, Jesús Pérez-Gil, José Requejo-Isidro, Nerea Huarte, José L Nieva
Membrane fusion induced by the envelope glycoprotein enables the intracellular replication of HIV-1; hence, this process constitutes a major target for antiretroviral compounds. It has been proposed that peptides having propensity to interact with membrane interfaces might exert broad antiviral activity against enveloped viruses. To test this hypothesis, in this contribution we have analyzed the antiviral effects of peptides derived from the membrane-proximal external region and the transmembrane domain of the envelope glycoprotein subunit gp41, which display different degrees of interfacial hydrophobicity...
September 19, 2017: Biophysical Journal
Nicole Avakyan, Justin W Conway, Hanadi F Sleiman
Long-range ordering of DNA crossover tiles with blunt ends on lipid bilayers is investigated using atomic force microscopy. "Blunt-ended" tiles do not have single-stranded complementary ends, and thus instead of assembling via base-pairing, they can interact by π-stacking of their duplex ends. This work demonstrates that the balance of base π-stacking interactions between the ends of DNA duplexes, cholesterol-mediated DNA anchoring, and electrostatic DNA binding to supported lipid bilayers (SLBs) presents an opportunity to build dynamic materials with long-range order on a soft support...
August 21, 2017: Journal of the American Chemical Society
Anna N Bukiya, Alejandro M Dopico
Cholesterol-protein interactions are essential for the architectural organization of cell membranes and for lipid metabolism. While cholesterol-sensing motifs in transmembrane proteins have been identified, little is known about cholesterol recognition by soluble proteins. We reviewed the structural characteristics of binding sites for cholesterol and cholesterol sulfate from crystallographic structures available in the Protein Data Bank. This analysis unveiled key features of cholesterol-binding sites that are present in either all or the majority of sites: i) the cholesterol molecule is generally positioned between protein domains that have an organized secondary structure; ii) the cholesterol hydroxyl/sulfo group is often partnered by Asn, Gln, and/or Tyr, while the hydrophobic part of cholesterol interacts with Leu, Ile, Val, and/or Phe; iii) cholesterol hydrogen-bonding partners are often found on α-helices, while amino acids that interact with cholesterol's hydrophobic core have a slight preference for β-strands and secondary structure-lacking protein areas; iv) the steroid's C21 and C26 constitute the "hot spots" most often seen for steroid-protein hydrophobic interactions; v) common "cold spots" are C8-C10, C13, and C17, at which contacts with the proteins were not detected...
June 2017: Journal of Lipid Research
Garima Jaipuria, Andrei Leonov, Karin Giller, Suresh Kumar Vasa, Łukasz Jaremko, Mariusz Jaremko, Rasmus Linser, Stefan Becker, Markus Zweckstetter
Cholesterol is an important regulator of membrane protein function. However, the exact mechanisms involved in this process are still not fully understood. Here we study how the tertiary and quaternary structure of the mitochondrial translocator protein TSPO, which binds cholesterol with nanomolar affinity, is affected by this sterol. Residue-specific analysis of TSPO by solid-state NMR spectroscopy reveals a dynamic monomer-dimer equilibrium of TSPO in the membrane. Binding of cholesterol to TSPO's cholesterol-recognition motif leads to structural changes across the protein that shifts the dynamic equilibrium towards the translocator monomer...
March 30, 2017: Nature Communications
Cheng-Dong Li, Qin Xu, Ruo-Xu Gu, Jing Qu, Dong-Qing Wei
It is generally believed that the etiology of Alzheimer's disease (AD) is closely related to the amyloid-β polypeptides, produced from γ-secretase cleavage of C99. There is preliminary evidence that cholesterol directly activates γ-secretase cleavage of C99 through mechanisms that have not been understood so far. In this article, coarse-grained (CG) and all-atom (AT) simulations were employed to investigate the association between C99 and cholesterol, which is essential for our understanding of the role of cholesterol in the amyloidogenic pathway...
February 1, 2017: Physical Chemistry Chemical Physics: PCCP
Sara L Lawrence, Michael A Gorman, Susanne C Feil, Terrence D Mulhern, Michael J Kuiper, Adam J Ratner, Rodney K Tweten, Craig J Morton, Michael W Parker
Cholesterol-dependent cytolysins (CDCs) are a family of pore-forming toxins that punch holes in the outer membrane of eukaryotic cells. Cholesterol serves as the receptor, but a subclass of CDCs first binds to human CD59. Here we describe the crystal structures of vaginolysin and intermedilysin complexed to CD59. These studies, together with small-angle X-ray scattering, reveal that CD59 binds to each at different, though overlapping, sites, consistent with molecular dynamics simulations and binding studies...
September 6, 2016: Structure
Namrata Singh, Debasish Bhattacharyya
Microorganisms express a variety of proteases that degrade many proteins of the host body and subvert host immune response. While elucidating the mechanism/s of an immune stimulatory drug that contains bile lipid, regulation of proteolytic activity was investigated. The drug and bile lipids both stabilize Proteinase K, an aggressive protease of fungal origin against auto-digestion. Among the components of bile lipids, only cholesterol and its derivatives stabilize the enzyme. Biophysical evidences such as scattering of light, intrinsic and extrinsic fluorescence emission spectra, circular dichroism spectra, atomic force microscopy, and transmission electron microscopy images indicated that cholesterol and its derivatives interact with Proteinase K...
March 2017: Journal of Cellular Physiology
Masaru Mukai, Kerney Jebrell Glover, Steven L Regen
Two cholesterol recognition/interaction amino-acid consensus peptides, N-acetyl-LWYIKC-amide, and N-acetyl-CLWYIK-amide, have been coupled to exchangeable mimics of Chol (cholesterol) and Phos (1,2-dipalmitoyl-sn-glycerol-3-phospho-(1'rac-glycerol)) via disulfide bond formation. Equilibration between Chol and Phos via thiolate-disulfide interchange reactions has revealed that both peptides favor Chol as a nearest-neighbor in liquid-disordered (ld) bilayers to the same extent. In contrast, no Chol- or Phos-recognition could be detected by these peptides in analogous liquid-ordered (lo) bilayers...
June 21, 2016: Biophysical Journal
Vicente Martínez-Redondo, Paulo R Jannig, Jorge C Correia, Duarte M S Ferreira, Igor Cervenka, Jessica M Lindvall, Indranil Sinha, Manizheh Izadi, Amanda T Pettersson-Klein, Leandro Z Agudelo, Alfredo Gimenez-Cassina, Patricia C Brum, Karin Dahlman-Wright, Jorge L Ruas
Endurance and resistance exercise training induces specific and profound changes in the skeletal muscle transcriptome. Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) coactivators are not only among the genes differentially induced by distinct training methods, but they also participate in the ensuing signaling cascades that allow skeletal muscle to adapt to each type of exercise. Although endurance training preferentially induces PGC-1α1 expression, resistance exercise activates the expression of PGC-1α2, -α3, and -α4...
July 15, 2016: Journal of Biological Chemistry
Francisco J Barrantes, Jacques Fantini
Pentameric ligand-gated ion channels (pLGICs) and their lipid microenvironments appear to have acquired mutually adaptive traits along evolution: 1) the three-ring architecture of their transmembrane (TM) region; 2) the ability of the outermost TM ring to convey lipid signals to the middle ring, which passes them on to the central pore ring, and 3) consensus motifs for sterol recognition in all pLGICs. Hopanoids are triterpenoid fossil lipids that constitute invaluable biomarkers for tracing evolution at the molecular scale...
July 2016: Progress in Lipid Research
Mireia Pérez-Verdaguer, Jesusa Capera, Ramón Martínez-Mármol, Marta Camps, Núria Comes, Michael M Tamkun, Antonio Felipe
The spatial localization of ion channels at the cell surface is crucial for their functional role. Many channels localize in lipid raft microdomains, which are enriched in cholesterol and sphingolipids. Caveolae, specific lipid rafts which concentrate caveolins, harbor signaling molecules and their targets becoming signaling platforms crucial in cell physiology. However, the molecular mechanisms involved in such spatial localization are under debate. Kv1.3 localizes in lipid rafts and participates in the immunological response...
March 2, 2016: Scientific Reports
Jacques Fantini, Coralie Di Scala, Luke S Evans, Philip T F Williamson, Francisco J Barrantes
Cholesterol controls the activity of a wide range of membrane receptors through specific interactions and identifying cholesterol recognition motifs is therefore critical for understanding signaling receptor function. The membrane-spanning domains of the paradigm neurotransmitter receptor for acetylcholine (AChR) display a series of cholesterol consensus domains (referred to as "CARC"). Here we use a combination of molecular modeling, lipid monolayer/mutational approaches and NMR spectroscopy to study the binding of cholesterol to a synthetic CARC peptide...
February 26, 2016: Scientific Reports
Hai-Yun Li, Jing Wang, Fan Meng, Zhe-Kun Jia, Yang Su, Qi-Feng Bai, Ling-Ling Lv, Fu-Rong Ma, Lawrence A Potempa, Yong-Bin Yan, Shang-Rong Ji, Yi Wu
Most proinflammatory actions of C-reactive protein (CRP) are only expressed following dissociation of its native pentameric assembly into monomeric form (mCRP). However, little is known about what underlies the greatly enhanced activities of mCRP. Here we show that a single sequence motif, i.e. cholesterol binding sequence (CBS; a.a. 35-47), is responsible for mediating the interactions of mCRP with diverse ligands. The binding of mCRP to lipoprotein component ApoB, to complement component C1q, to extracellular matrix components fibronectin and collagen, to blood coagulation component fibrinogen, and to membrane lipid component cholesterol, are all found to be markedly inhibited by the synthetic CBS peptide but not by other CRP sequences tested...
April 15, 2016: Journal of Biological Chemistry
Jin-Feng Zhao, Song-Kun Shyue, Tzong-Shyuan Lee
Excess nitric oxide (NO) deregulates cholesterol metabolism in macrophage foam cells, yet the underlying molecular mechanism is incompletely understood. To investigate the mechanism, we found that in macrophages, treatment with NO donors S-nitroso-N-acetyl-D,L-penicillamine (SNAP) or diethylenetriamine/nitric oxide induced LXRα degradation and reduced the expression of the downstream target of LXRα, ATP-binding cassette transporter A1 (ABCA1), and cholesterol efflux. In addition, SNAP induced calcium (Ca(2+)) influx into cells, increased calpain activity and promoted the formation of calpain-LXRα complex...
2016: International Journal of Biological Sciences
Andrew M Ellisdon, Cyril F Reboul, Santosh Panjikar, Kitmun Huynh, Christine A Oellig, Kelly L Winter, Michelle A Dunstone, Wayne C Hodgson, Jamie Seymour, Peter K Dearden, Rodney K Tweten, James C Whisstock, Sheena McGowan
The lethal factor in stonefish venom is stonustoxin (SNTX), a heterodimeric cytolytic protein that induces cardiovascular collapse in humans and native predators. Here, using X-ray crystallography, we make the unexpected finding that SNTX is a pore-forming member of an ancient branch of the Membrane Attack Complex-Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily. SNTX comprises two homologous subunits (α and β), each of which comprises an N-terminal pore-forming MACPF/CDC domain, a central focal adhesion-targeting domain, a thioredoxin domain, and a C-terminal tripartite motif family-like PRY SPla and the RYanodine Receptor immune recognition domain...
December 15, 2015: Proceedings of the National Academy of Sciences of the United States of America
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