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1.
Proteins ; 78(2): 365-80, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19722269

RESUMO

Ubiquitination plays an important role in many cellular processes and is implicated in many diseases. Experimental identification of ubiquitination sites is challenging due to rapid turnover of ubiquitinated proteins and the large size of the ubiquitin modifier. We identified 141 new ubiquitination sites using a combination of liquid chromatography, mass spectrometry, and mutant yeast strains. Investigation of the sequence biases and structural preferences around known ubiquitination sites indicated that their properties were similar to those of intrinsically disordered protein regions. Using a combined set of new and previously known ubiquitination sites, we developed a random forest predictor of ubiquitination sites, UbPred. The class-balanced accuracy of UbPred reached 72%, with the area under the ROC curve at 80%. The application of UbPred showed that high confidence Rsp5 ubiquitin ligase substrates and proteins with very short half-lives were significantly enriched in the number of predicted ubiquitination sites. Proteome-wide prediction of ubiquitination sites in Saccharomyces cerevisiae indicated that highly ubiquitinated substrates were prevalent among transcription/enzyme regulators and proteins involved in cell cycle control. In the human proteome, cytoskeletal, cell cycle, regulatory, and cancer-associated proteins display higher extent of ubiquitination than proteins from other functional categories. We show that gain and loss of predicted ubiquitination sites may likely represent a molecular mechanism behind a number of disease-associatedmutations. UbPred is available at http://www.ubpred.org.


Assuntos
Proteoma/análise , Proteínas de Saccharomyces cerevisiae/análise , Saccharomyces cerevisiae/metabolismo , Proteínas Ubiquitinadas/análise , Sequência de Aminoácidos , Bases de Dados de Proteínas , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Humanos , Espectrometria de Massas , Dados de Sequência Molecular , Proteoma/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Análise de Sequência de Proteína , Complexos Ubiquitina-Proteína Ligase/metabolismo , Proteínas Ubiquitinadas/metabolismo , Ubiquitinação
2.
J Proteome Res ; 6(6): 2176-85, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17503796

RESUMO

The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFalpha) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFalpha- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFalpha and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune response. The contrasting responses to LPS indicate that TNFalpha and IL-1 regulate different processes. A large-scale proteomic analysis of TNFalpha- and IL-1-induced responses was undertaken to identify processes uniquely regulated by TNFalpha and IL-1. When combined with genomic studies, our results indicate that TNFalpha, but not IL-1, mediates cell cycle arrest.


Assuntos
Genômica , Interleucina-1/farmacologia , Proteômica , Fator de Necrose Tumoral alfa/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Citoplasma/genética , Citoplasma/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Proteínas/análise , Proteínas/genética , RNA Mensageiro/análise , Transcrição Gênica/efeitos dos fármacos
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