What is nephrocalcinosis?

Kidney International, Journal Year: 2015, Volume and Issue: 88(1), P. 35 - 43

Published: March 25, 2015

Language: Английский

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Casein kinases as potential therapeutic targets

Expert Opinion on Therapeutic Targets, Journal Year: 2015, Volume and Issue: 20(3), P. 319 - 340

Published: Nov. 13, 2015

Introduction: The conventional term ‘casein kinase’ (CK) denotes three classes of kinases – CK1, CK2 and Golgi-CK (G-CK)/Fam20C (family with sequence similarity 20, member C) sharing the ability to phoshorylate casein in vitro, but otherwise unrelated each other. All CKs have been reported be implicated human diseases, reviews individually dealing druggability CK1 are available. Our aim is provide a comparative analysis as therapeutic targets.Areas covered: CK for which implication neoplasia best documented, survival cancer cells often relying on its overexpression. An ample variety cell-permeable inhibitors developed, couple these now clinical trials. Isoform-specific that expected play beneficial role oncology neurodegeneration also developed. In contrast, pathogenic potential G-CK/Fam20C caused by loss function. Activators Fam20C, notably sphingolipids their analogs, may prove this respect.Expert opinion: Optimization will useful develop new strategies treating neurodegenerative disorders, while design potent activators tool fields bio-mineralization hypophosphatemic diseases.

Language: Английский

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The secret life of kinases: insights into non-catalytic signalling functions from pseudokinases

Biochemical Society Transactions, Journal Year: 2017, Volume and Issue: 45(3), P. 665 - 681

Published: June 15, 2017

Over the past decade, our understanding of mechanisms by which pseudokinases, comprise ∼10% human and mouse kinomes, mediate signal transduction has advanced rapidly with increasing structural, biochemical, cellular genetic studies. Pseudokinases are catalytically defective counterparts conventional, active protein kinases have been attributed functions as interaction domains acting variously allosteric modulators conventional other enzymes, regulators trafficking or localisation, hubs to nucleate assembly signalling complexes, transmembrane effectors such functions. Here, categorising mammalian pseudokinases based on their known functions, we illustrate mechanistic diversity among these proteins, can be viewed a window into non-catalytic that exerted kinases.

Language: Английский

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Site-specific O-Glycosylation Analysis of Human Blood Plasma Proteins

Molecular & Cellular Proteomics, Journal Year: 2015, Volume and Issue: 15(2), P. 624 - 641

Published: Nov. 24, 2015

Site-specific glycosylation analysis is key to investigate structure-function relationships of glycoproteins, e.g. in the context antigenicity and disease progression. The analysis, though, quite challenging time consuming, particular for O-glycosylated proteins. In consequence, despite their clinical biopharmaceutical importance, many human blood plasma glycoproteins have not been characterized comprehensively with respect O-glycosylation. Here, we report on site-specific O-glycosylation glycoproteins. To this end pooled healthy donors was proteolytically digested using a broad-specific enzyme (Proteinase K), followed by precipitation step, as well glycopeptide enrichment fractionation step via hydrophilic interaction liquid chromatography, latter being optimized intact O-glycopeptides carrying short mucin-type core-1 -2 O-glycans, which represent vast majority O-glycans Enriched O-glycopeptide fractions were subjected mass spectrometric reversed-phase chromatography coupled online an ion trap spectrometer operated positive-ion mode. Peptide identity glycan composition derived from low-energy collision-induced dissociation fragment spectra acquired multistage pinpoint sites glycopeptides fragmented electron transfer dissociation. Spectra annotated database searches manually. Overall, 31 regions belonging 22 proteins identified, acute-phase Strikingly, also 11 novel identified. total 23 could be pinpointed. Interestingly, use Proteinase K proved particularly beneficial context. identified O-glycan compositions most probably correspond mono- disialylated (T-antigen). developed workflow allows identification characterization major population O-glycoproteome our results provide new insights, can help unravel relationships. data deposited ProteomeXchange PXD003270. Human harbors arguably complex yet informative proteome present body (1.Anderson N.L. Plasma Proteome: History, Character, Diagnostic Prospects.Mol. Cell. Proteomics. 2002; 1: 845-867Abstract Full Text PDF PubMed Scopus (3559) Google Scholar). A significant impact its relevance diagnostic potential attributed features functions plethora (60–80 mg protein per ml plasma), covering dynamic concentration range more than ten orders magnitude (2.Schaller J. Gerber S. Kämpfer U. Lejon Trachsel C. Blood Proteins.Human Proteins. John Wiley & Sons, Ltd, 2008: 17-20Crossref majority, that 99%, these are classical proteins, like albumins, (immuno)globulins, clotting factors, complement system; however, lower abundant but—no less meaningful—fraction nonclassical comprises multitude cytokines tissue leakage Several studies show qualitative quantitative alterations (and peptides)—analyzed individually or entirety (or peptidome)—can directly reflect pathophysiological states, serve biomarkers onset progression number diseases (3.Anderson L. Six decades searching meaning proteome.J. 2014; 107: 24-30Crossref (36) Scholar, 4.Ceciliani F. Pocacqua V. acute phase alpha1-acid glycoprotein: model altered during diseases.Curr. Protein Pept. Sci. 2007; 8: 91-108Crossref (173) 5.Polanski M. Anderson list candidate cancer targeted proteomics.Biomark Insights. 1-48PubMed recent years focus in-depth analyses has evolved quantification entire peptidome) (6.Anderson Hunter C.L. Quantitative multiple reaction monitoring assays proteins.Mol. 2006; 5: 573-588Abstract (1080) 7.Farrah T. Deutsch E.W. Omenn G.S. Campbell D.S. Sun Z. Bletz J.A. Mallick P. Katz J.E. Malmstrom Ossola R. Watts J.D. Lin B. Zhang H. Moritz R.L. Aebersold high-confidence reference set estimated concentrations PeptideAtlas.Mol. 2011; 10 (M110 006353)Abstract (357) 8.Haab B.B. Geierstanger B.H. Michailidis G. Vitzthum Forrester Okon Saviranta Brinker A. Sorette Perlee Suresh Drwal Adkins J.N. Immunoassay antibody microarray HUPO Proteome Project specimens: Systematic variation between sample types calibration spectrometry data.Proteomics. 2005; 3278-3291Crossref (130) 9.Hortin G.L. Sviridov D. High-abundance polypeptides comprising top 4 logs polypeptide abundance.Clin. Chem. 2008; 54: 1608-1616Crossref (215) 10.Schenk Schoenhals G.J. de Souza Mann high confidence, manually validated set.BMC Med Genomics. 41Crossref Scholar) toward subproteomes interactome (11.Zhou Lucas D.A. Chan K.C. Issaq H.J. Petricoin Iii E.F. Liotta L.A. Veenstra T.D. Conrads T.P. An investigation into serum "interactome".Electrophoresis. 2004; 25: 1289-1298Crossref (281) Scholar), phosphoproteome (12.Carrascal Gay Ovelleiro Casas Gelpí E. Abian Characterization linear search engines.J. Res. 2010; 9: 876-884Crossref (47) 13.Zawadzka A.M. Schilling Cusack M.P. Sahu A.K. Drake Fisher S.J. Benz C.C. Gibson B.W. Phosphoprotein secretome tumor cells source candidates breast plasma.Mol. 13: 1034-1049Abstract (38) glycoproteome (14.Kim Y.J. Zaidi-Ainouch Gallien Domon Mass spectrometry-based detection selective monitoring.Nat. Protoc. 2012; 7: 859-871Crossref (30) received interest years, because N- and/or Although comprehensive N-glycoproteome already advanced (15.Pasing Y. Sickmann Lewandrowski N-glycoproteomics: site annotation.Biol. 393: 249-258Crossref (29) even samples (16.Lee Cha Lim J.S. Lee S.H. Song S.Y. Kim Hancock W.S. Yoo Paik Y.K. Abundance-ratio-based semiquantitative N-linked hepatocellular carcinoma patients.J. 2328-2338Crossref (31) 17.Zielinska D.F. Gnad Wisniewski J.R. Precision mapping vivo reveals rigid topological sequence constraints.Cell. 141: 897-907Abstract (706) similar - though equally important relevant still lagging behind. ubiquitously found functionally form O-glycosylation, shown O-glycan-related (clinical) (18.Pacchiarotta Hensbergen P.J. Wuhrer van Nieuwkoop Nevedomskaya Derks R.J. Schoenmaker Koeleman C.A. Dissel Deelder Mayboroda O.A. Fibrinogen alpha chain possible markers urinary tract infection.J. 75: 1067-1073Crossref (26) 19.Gomes Almeida Ferreira Silva Santos-Sousa Pinto-de-Sousa Santos L.L. Amado Schwientek Levery S.B. Mandel Clausen David Reis Osorio Glycoproteomic patients gastric precancerous lesions.J. 2013; 12: 1454-1466Crossref (59) 20.Cazet Julien Bobowski Burchell Delannoy Tumour-associated carbohydrate antigens cancer.Breast Cancer 204Crossref (180) 21.Dube D.H. Bertozzi C.R. Glycans inflammation–potential therapeutics diagnostics.Nat. Rev. Drug Discov. 4: 477-488Crossref (1356) 22.Rhodes B.J. Yu L.-G. Glycosylation Disease.eLS. 2010Crossref 23.Ju Wang Aryal R.P. Lehoux S.D. Ding X. Kudelka M.R. Cutler Zeng Heimburg-Molinaro Smith Cummings R.D. Tn sialyl-Tn antigens, aberrant O-glycomics markers.Proteomics Clin. Appl. 618-631Crossref (107) O-glycosyation (O-GalNAc), core-2 (24.Hanisch F.G. mucin type.Biol. 2001; 382: 143-149Crossref (270) 25.Yabu Korekane Miyamoto Precise structural O-linked oligosaccharides serum.Glycobiology. 24: 542-553Crossref (32) predominantly clustered occurrence described confer overall stability proteolytic protection (26.Jentoft N. Why O-glycosylated?.Trends Biochem. 1990; 15: 291-294Abstract (626) Apart global impact, link presence proximity regulatory domains proteolysis events involved maturation (proprotein-convertase-processing) (27.Steentoft Vakhrushev Joshi Kong Vester-Christensen M.B. Schjoldager K.T. Lavrsen K. Dabelsteen Pedersen N.B. Marcos-Silva Gupta Bennett E.P. Brunak Wandall H.H. O-GalNAc through SimpleCell technology.EMBO 32: 1478-1488Crossref (916) better understand protective capabilities move function required. One main obstacles relates lack predictable consensus-motif within peptide backbone it N-glycans (28.Jensen P.H. Kolarich Packer N.H. Mucin-type O-glycosylation–putting pieces together.FEBS 277: 81-94Crossref (184) initial attachment N-acetylgalactosamine monosaccharide hydroxyl group either serine threonine, but tyrosine hydroxylysine, governed family 20 distinct GalNAc-transferase isoenzymes (GalNAc-Ts) different partially overlapping specificities expression patterns. This regulation, turn, contributes complexity O-glycoproteome. However, previous primarily attached threonine content serine, proline (Ser/Thr-X-X-Pro, Ser/Thr-P Pro-Ser/Thr) (29.Strous Dekker glycoproteins.Crit. Mol. Biol. 1992; 27: 57-92Crossref (770) 30.Halim Ruetschi Larson Nilsson LC-MS/MS structures cerebrospinal fluid glycoproteins.J. 573-584Crossref (91) As postfolding event, taking place Golgi apparatus, depended surface accessibility thus coil, linker (31.Julenius Molgaard Prediction, conservation mammalian sites.Glycobiology. 153-164Crossref (775) Additional confounding factors universal endo-O-glycosidase enables release proteins; chemical methods do exist proven core technique analyses. generic O-glycoproteomic usually starts isolation, prefractionation single glycoprotein subsequent steps, (glyco)peptides generated digestion specific proteases trypsin. this, broad- nonspecific Pronase E successfully employed (32.Zauner HILIC-LC-MS K-generated O-glycopeptides.J. Sep. 33: 903-910Crossref (87) 33.Nwosu Seipert R.R. Strum Hua S.S. Zivkovic German Lebrilla C.B. Simultaneous extensive mixtures.J. 10: 2612-2624Crossref (109) 34.Hua Hu C.Y. Totten S.M. Oh M.J. Yun Nwosu Glyco-analytical multispecific (Glyco-AMP): simple method detailed characterization.J. 4414-4423Crossref (39) Essential nearly every glycoproteomic approach removal high-abundant interfering nonglycosylated peptides glycopeptides. repertoire separation techniques covers solid extraction based such (HILIC) (35.Alpert A.J. Shukla Zieske L.R. Yuen S.W. Ferguson M.A.J Mehlert Pauly Orlando Hydrophilic-interaction carbohydrates.J. Chromatogr. 1994; 676: 191-202Crossref (216) 36.Zauner Recent advances glycomics.Electrophoresis. 3456-3466Crossref (147) frequently used setup measurement enriched (LC) 1The abbreviations are:LCliquid chromatographyECDElectron-capture dissociationETDElectron-transfer dissociationFT-ICRFourier transform cyclotron resonanceHILICHydrophilic chromatographyIAAIodoacetamideICCIon charge controlLTQLinear quadrupole. electrospray ionization tandem (LC-ESI-MS/MS). instrumentation, development electron-transfer/electron-capture (ETD/ECD) (37.Hanisch O-glycoproteomics: O-glycoprotein CID/ETD top-down Sequencing In-Source Decay MALDI Spectrometry.Methods : 179-189Crossref (15) 38.Alley Jr., W.R. Mechref Novotny M.V. combining electron-transfer data.Rapid Commun. Spectrom. 2009; 23: 161-170Crossref (128) resolution orbital analyzers, paved way thousands occupied recently (17.Zielinska 27.Steentoft Combined workflows ETD/ECD fragmentation along (multistage, MSn) high- low collisional induced energy (HCD/CID) compositional (structural) information moiety (39.Saba Dutta Hemenway Viner Increasing Productivity Glycopeptides Analysis Using Higher-Energy Collision Dissociation-Accurate Mass-Product-Dependent Electron Transfer Dissociation.Int. 2012: 7Crossref 40.Singh Zampronio C.G. Creese Cooper Higher collision (HCD) product ion-triggered (ETD) 11: 4517-4525Crossref (129) driven O-glycoproteomics reviewed detail elsewhere (41.Thaysen-Andersen Advances LC-MS/MS-based glycoproteomics: Getting closer system-wide O-glycoproteome.Biochim. Biophys. Acta. 1844: 1437-1452Crossref (170) 42.Levery Steentoft Halim Narimatsu O-glycoproteomics.Biochim. 1850: 33-42Crossref (94) Owing amount bioinformatic software tools prediction assisted interpretation annotation (43.Dallas D.C. Martin W.F. J.B. Automated analysis–review current state future directions.Brief. Bioinform. 14: 361-374Crossref (66) 44.Wu Pu T.H. Khoo K.H. Novel LC-MS2 dependent parallel acquisition sequencing glycopeptides.Anal. 86: 5478-5486Crossref (72) Moreover, reporting guidelines collecting, sharing, integrating, interpreting glycomics specified MIRAGE consortium (minimum required experiment) (45.Kolarich Rapp Struwe W.B. Haslam Zaia McBride Agravat Kato Ranzinger Kettner York minimum experiment (MIRAGE) project: improving standards mass-spectrometry-based glycoanalytic data.Mol. 991-995Abstract 46.York Aoki-Kinoshita K.F. Costello C.E. Dell Feizi Karlsson Liu Paulson J.C. Rudd P.M. Tiemeyer Wells MIRAGE: experiment.Glycobiology. 402-406Crossref (85) Electron-capture Electron-transfer Fourier resonance Hydrophilic Iodoacetamide Ion control Linear aim study develop explorative nontargeted known carry mainly O-glycans. achieve combined offline-HILIC nano-reversed-phase ion-trap (nanoRP-LC-ESI-IT-MS: CID-MS2/-MS3, ETD-MS2). applied donors. Based O-glycopeptides, able characterize (i.e. peptide, site, O-glycans) including fibrinogen plasminogen. revealed exclusively O-glycopeptides. few All chemicals solvents highest purity available. Purified water preparation HILIC freshly prepared Milli-Q purification system (referred "Milli-Q water", 18.2 mΩ × cm−1 at 25 °C, Total Organic Carbon 3 ppb; Merck Millipore, Darmstadt, Germany). For LC-MS ultrapure used, same equipped additional filter MS"; LC-Pak Polisher, Millipore). (pooled sample, donors) purchased Affinity Biologicals Inc. (VisuCon-F, Frozen Normal Control Blood, FRNCP0125; Ancaster, ON, Canada). μl (about 2 protein) 100 mm ammonium bicarbonate(aq) (NH4HCO3, pH 8.0) (Sigma Aldrich, Steinheim, Germany) added obtain final 50 NH4HCO3(aq) (pH 8.0). Disulfide bonds reduced addition 6.25 1,4-dithiothreitol (DTT; Sigma Aldrich) dissolved 8.0), DTT. incubated 45 min 60 subsequently allowed cool down room temperature. Cystein alkylation achieved 12.5 iodoacetamide (IAA; 16.67 IAA. temperature under light exclusion. quenched 2.5 DTT 3.75 before placing fluorescent lamp (gas-discharge lamp) 15 decompose light-sensitive By adding 169 brought volume 250 μl. Proteolytic Aldrich), protease broad specificity cleaves after aliphatic, aromatic hydrophobic amino acids. buffer) supplemented 66 μg 122 order enzyme/protein ratio 1:30 (w/w, 0.033 protein). 16 h 37 °C gentle agitation (200 rpm). post-digestion cleanup precipitated acetonitrile (ACN; Aldrich). four volumes ACN centrifuged 2880 g (Centrifuge 5804 R; Eppendorf, Hamburg, supernatant transferred dried vacuum centrifugation (RVC 2–33 CDplus, ALPHA 2–4 LDplus; Christ GmbH, Osterode am Harz, digest resuspended 500 80% (v/v, 20,238 remove any particles 5424; Eppendorf). supernatant, containing about glycopeptides, HILIC-HPLC (UltiMate™ Nano HPLC-System: Thermo Scientific/Dionex, Dreieich, Germany; Column: ACQUITY UPLC BEH Column, 130Å, 1.7 μm, 2.1 X mm; Waters, Manchester, UK) enrichment. HPLC binary gradient 100% (v/v; solvent A) formate(aq) (NH4FA, 4.4; B, After injection (500 μl) 20% B isocratically 5 min, 50% both constant flow rate μl/min. Subsequently, went 90% 1 while reducing 150 wash column kept 9 min. Column re-equilibration isocratic elution min; (the increased μl/min min). During 40 °C. profile monitored UV absorption 214 nm. Fractions collected mins 0 34 reconstituted water. analyzed nano-LC-MSn Ultimate3000 nanoHPLC (Thermo Scientific/Dionex) (AmaZon ETD, Bruker Daltonics, Bremen, Within first injection, loaded C18 μ-precolumn (Acclaim PepMap100, C18, Å, 300 μm i.d. Scientific/Dionex). pre-concentration desalting "loading pump 1" (98% MS, 2% ACN, 0.05% trifluoroacetic acid Aldrich)) u

Language: Английский

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Crystal structure of the Golgi casein kinase

Proceedings of the National Academy of Sciences, Journal Year: 2013, Volume and Issue: 110(26), P. 10574 - 10579

Published: June 10, 2013

The family with sequence similarity 20 (Fam20) kinases phosphorylate extracellular substrates and play important roles in biomineralization. Fam20C is the Golgi casein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs. Mutations cause Raine syndrome, an osteosclerotic bone dysplasia. Here we report crystal structure of ortholog from Caenorhabditis elegans. nucleotide-free Mn/ADP-bound structures unveil atypical protein kinase-like fold highlight residues critical for activity. position regulatory αC helix lack activation loop indicate architecture primed efficient catalysis. Furthermore, several distinct elements, including presence disulfide bonds, suggest Fam20 diverged early evolution superfamily. Our results reinforce structural diversity have implications patients disorders

Language: Английский

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Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain

PLoS Biology, Journal Year: 2017, Volume and Issue: 15(7), P. e2002457 - e2002457

Published: July 18, 2017

Extracellular phosphorylation of proteins was suggested in the late 1800s when it demonstrated that casein contains phosphate. More recently, extracellular kinases phosphorylate serine, threonine, and tyrosine residues numerous have been identified. However, functional significance specific nervous system is poorly understood. Here we show synaptic accumulation GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) pathological pain are controlled by ephrin-B-induced a single (p*Y504) highly conserved region fibronectin type III (FN3) domain receptor kinase EphB2. Ligand-dependent Y504 modulates EphB-NMDAR interaction cortical spinal cord neurons. Furthermore, enhances NMDAR localization injury-induced behavior. By mediating inducible interactions capable modulating animal behavior, EphBs may represent previously unknown class mechanism protein function.

Language: Английский

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Structure and evolution of the Fam20 kinases

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: March 19, 2018

The Fam20 proteins are novel kinases that phosphorylate secreted and proteoglycans. Fam20C phosphorylates hundreds of is activated by the pseudokinase Fam20A. Fam20B a xylose residue to regulate proteoglycan synthesis. Despite these wide-ranging important functions, molecular structural basis for regulation substrate specificity unknown. Here we report characterizations all three kinases, show formation an evolutionarily conserved homodimer or heterodimer with has unique active site recognizing Galβ1-4Xylβ1, initiator disaccharide within tetrasaccharide linker region We further in animals monomeric preceded appearance dimeric Fam20C, dimerization trait emerged concomitantly change specificity. Our results provide comprehensive structural, biochemical, evolutionary insights into function kinases.

Language: Английский

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The Lottia gigantea shell matrix proteome: re-analysis including MaxQuant iBAQ quantitation and phosphoproteome analysis

Proteome Science, Journal Year: 2014, Volume and Issue: 12(1), P. 28 - 28

Published: Jan. 1, 2014

Although the importance of proteins biomineral organic matrix and their posttranslational modifications for biomineralization is generally recognized, number published proteomes still small. This mostly due to lack comprehensive sequence databases, usually derived from genomic sequencing projects. However, in-depth mass spectrometry-based proteomic analysis, which critically depends on high-quality a very fast tool identify candidates functional modifications. Identification such candidate facilitated by at least approximate quantitation identified proteins, because most abundant ones may also be interesting further analysis.Re-quantification previously Lottia shell using intensity-based absolute quantification (iBAQ) method as implemented in MaxQuant identification software showed that only 57 382 accepted identifications constituted 98% total proteome. group did not contain obvious intracellular cytoskeletal components or ribosomal invariably minor high-throughput proteomes. Fourteen these major were phosphorylated variable extent. All together we 52 phospho sites 20 with high confidence.We show iBAQ useful narrow down protein research cell biology, genetics materials research. Knowledge could valuable addition true especially phosphorylation, this modification was already shown modify mineralization processes some instances.

Language: Английский

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Phosphorylation of spore coat proteins by a family of atypical protein kinases

Proceedings of the National Academy of Sciences, Journal Year: 2016, Volume and Issue: 113(25)

Published: May 16, 2016

Significance The posttranslational modification of proteins with a molecule phosphate, termed protein phosphorylation, is mechanism used by cells to regulate cellular activities. Protein phosphorylation occurs in all life forms and catalyzed superfamily enzymes known as kinases. Using bioinformatics, we have identified family spore coat (Cot) kinases, which are related the secreted kinase, sequence similarity 20C (Fam20C). founding member this CotH from spore-forming bacterium Bacillus subtilis . We show that CotH-dependent CotB CotG necessary for proper germination spores. Because several CotH-containing organisms human pathogens, our work has important clinical implications combat diseases, such anthrax.

Language: Английский

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Spatiotemporally resolved subcellular phosphoproteomics

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(25)

Published: June 16, 2021

Significance As one of the most important post-translational modifications, phosphorylation is both highly abundant and dynamically regulated in cells. Characterizing subcellular phosphoproteome with high temporal resolution should shed light on their contributions to diverse cellular processes. By integrating an activatable proximity labeling enzyme orthogonal enrichment scheme, we have developed SubMAPP strategy for mapping dynamics proteome living systems. The sensitivity enabled identification phosphoproteins sites endoplasmic reticulum (ER), revealing ER-to-mitochondria protein translocation under ER stress.

Language: Английский

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