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Journal articleSerwa R, Krause E, Abaitua F, et al., 2015,
Systems analysis of protein fatty acylation in herpes simplex virus infected cells using chemical proteomics.
, Chemistry & Biology, Vol: 22, Pages: 1008-1017, ISSN: 1074-5521Protein fatty acylation regulates diverse aspects of cellular function and organization and plays a key role in host immune responses to infection. Acylation also modulates the function and localization of virus-encoded proteins. Here, we employ chemical proteomics tools, bio-orthogonal probes, and capture reagents to study myristoylation and palmitoylation during infection with herpes simplex virus (HSV). Using in-gel fluorescence imaging and quantitative mass spectrometry, we demonstrate a generalized reduction in myristoylation of host proteins, whereas palmitoylation of host proteins, including regulators of interferon and tetraspanin family proteins, was selectively repressed. Furthermore, we found that a significant fraction of the viral proteome undergoes palmitoylation; we identified a number of virus membrane glycoproteins, structural proteins, and kinases. Taken together, our results provide broad oversight of protein acylation during HSV infection, a roadmap for similar analysis in other systems, and a resource with which to pursue specific analysis of systems and functions.
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Journal articleNickel S, Serwa RA, Kaschani F, et al., 2015,
Chemoproteomic Evaluation of the Polyacetylene Callyspongynic Acid
, Chemistry-A European Journal, Vol: 21, Pages: 10721-10728, ISSN: 1521-3765Polyacetylenes are a class of alkyne-containing natural products. Although potent bioactivities and thus possible applications as chemical probes have already been reported for some polyacetylenes, insights into the biological activities or molecular mode of action are still rather limited in most cases. To overcome this limitation, we describe the application of the polyacetylene callyspongynic acid in the development of an experimental roadmap for characterizing potential protein targets of alkyne-containing natural products. To this end, we undertook the first chemical synthesis of callyspongynic acid. We then used in situ chemical proteomics methods to demonstrate extensive callyspongynic acid-mediated chemical tagging of endoplasmic reticulum-associated lipid-metabolizing and modifying enzymes. We anticipate that an elucidation of protein targets of natural products may serve as an effective guide to the development of subsequent biological assays that aim to identify chemical phenotypes and bioactivities.
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Journal articleBroncel M, Serwa RA, Ciepla P, et al., 2015,
Myristoylation profiling in human cells and zebrafish.
, Data in Brief, Vol: 4, Pages: 379-383, ISSN: 2352-3409Human cells (HEK 293, HeLa, MCF-7) and zebrafish embryos were metabolically tagged with an alkynyl myristic acid probe, lysed with an SDS buffer and tagged proteomes ligated to multifunctional capture reagents via copper-catalyzed alkyne azide cycloaddition (CuAAC). This allowed for affinity enrichment and high-confidence identification, by delivering direct MS/MS evidence for the modification site, of 87 and 61 co-translationally myristoylated proteins in human cells and zebrafish, respectively. The data have been deposited to ProteomeXchange Consortium (Vizcaíno et al., 2014 Nat. Biotechnol., 32, 223-6) (PXD001863 and PXD001876) and are described in detail in Multifunctional reagents for quantitative proteome-wide analysis of protein modification in human cells and dynamic protein lipidation during vertebrate development׳ by Broncel et al., Angew. Chem. Int. Ed.
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Journal articleBroncel M, Serwa RA, Ciepla P, et al., 2015,
Multifunctional Reagents for Quantitative Proteome-Wide Analysis of Protein Modification in Human Cells and Dynamic Profiling of Protein Lipidation During Vertebrate Development
, Angewandte Chemie-International Edition, Vol: 54, Pages: 5948-5951, ISSN: 1521-3773Novel multifunctional reagents were applied incombination with a lipid probe for affinity enrichment ofmyristoylated proteins and direct detection of lipid-modifiedtryptic peptides by mass spectrometry. This method enableshigh-confidence identification of the myristoylated proteomeon an unprecedented scale in cell culture, and allowed the firstquantitative analysis of dynamic changes in protein lipidationduring vertebrate embryonic development.
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Journal articleYusuf NA, Green JL, Wall RJ, et al., 2015,
The Plasmodium Class XIV Myosin, MyoB, Has a Distinct Subcellular Location in Invasive and Motile Stages of the Malaria Parasite and an Unusual Light Chain
, Journal of Biological Chemistry, Vol: 290, Pages: 12147-12164, ISSN: 1083-351XMyosin B (MyoB) is one of the two short class XIV myosinsencoded in the Plasmodium genome. Class XIV myosins arecharacterized by a catalytic “head,” a modified “neck,” and theabsence of a “tail” region. Myosin A (MyoA), the other class XIVmyosin in Plasmodium, has been established as a component ofthe glideosome complex important in motility and cell invasion,but MyoB is not well characterized. We analyzed the propertiesof MyoB using three parasite species as follows: Plasmodiumfalciparum, Plasmodium berghei, and Plasmodium knowlesi.MyoB is expressed in all invasive stages (merozoites, ookinetes,and sporozoites) of the life cycle, and the protein is found in adiscrete apical location in these polarized cells. In P. falciparum,MyoB is synthesized very late in schizogony/merogony, and itslocation in merozoites is distinct from, and anterior to, that of arange of known proteins present in the rhoptries, rhoptry neckor micronemes. Unlike MyoA, MyoB is not associated withglideosome complex proteins, including the MyoA light chain,myosin A tail domain-interacting protein (MTIP). A uniqueMyoB light chain (MLC-B) was identified that contains a calmodulin-likedomain at the C terminus and an extended N-terminalregion. MLC-B localizes to the same extreme apical polein the cell as MyoB, and the two proteins form a complex. Wepropose that MLC-B is a MyoB-specific light chain, and for theshort class XIV myosins that lack a tail region, the atypical myosinlight chains may fulfill that role.
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Journal articleMasumoto N, Lanyon-Hogg T, Rodgers UR, et al., 2015,
Membrane bound O-acyltransferases and their inhibitors
, Biochemical Society Transactions, Vol: 43, Pages: 246-252, ISSN: 1470-8752Since the identification of the membrane-bound O-acyltransferase (MBOATs) protein family in the early2000s, three distinct members [porcupine (PORCN), hedgehog (Hh) acyltransferase (HHAT) and ghrelin Oacyltransferase(GOAT)] have been shown to acylate specific proteins or peptides. In this review, topologydetermination, development of assays to measure enzymatic activities and discovery of small moleculeinhibitors are compared and discussed for each of these enzymes.
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Journal articleCiepla P, Magee AI, Tate EW, 2015,
Cholesterylation: a tail of hedgehog
, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 43, Pages: 262-267, ISSN: 0300-5127- Author Web Link
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- Citations: 12
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Journal articleWright MH, Paape D, Storck EM, et al., 2015,
Global Analysis of Protein <i>N</i>-Myristoylation and Exploration of <i>N</i>-Myristoyltransferase as a Drug Target in the Neglected Human Pathogen <i>Leishmania donovani</i>
, CHEMISTRY & BIOLOGY, Vol: 22, Pages: 342-354, ISSN: 1074-5521- Author Web Link
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- Citations: 63
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Journal articleLanyon-Hogg T, Ritzefeld M, Masumoto N, et al., 2015,
Modulation of Amide Bond Rotamers in 5-Acyl-6,7-dihydrothieno[3,2-c]pyridines
, Journal of Organic Chemistry, Vol: 80, Pages: 4370-4377, ISSN: 1520-69042-Substituted N-acyl-piperidine is a widespread and important structuralmotif, found in approximately 500 currently available structures, and present in nearly30 pharmaceutically active compounds. Restricted rotation of the acyl substituent insuch molecules can give rise to two distinct chemical environments. Here wedemonstrate, using NMR studies and density functional theory modeling of the lowestenergy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that the amideE:Z equilibrium is affected by non-covalent interactions between the amide oxygen andadjacent aromatic protons. Structural predictions were used to design molecules that promote either the E- or Z-amideconformation, enabling preparation of compounds with a tailored conformational ratio, as proven by NMR studies. Analysis ofthe available X-ray data of a variety of published N-acyl-piperidine-containing compounds further indicates that these moleculesare also clustered in the two observed conformations. This finding emphasizes that directed conformational isomerism hassignificant implications for the design of both small molecules and larger amide-containing molecular architectures.
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Journal articleKonitsiotis AD, Jovanovic B, Ciepla P, et al., 2015,
Topological Analysis of Hedgehog Acyltransferase, a Multipalmitoylated Transmembrane Protein
, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 290, Pages: 3293-3307- Author Web Link
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- Citations: 46
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