Technologies for PTM discovery and functional mapping p. 505
Technologies for PTM discovery and functional mapping p. 505
批准号:
8998786
负责人:
David J Pagliarini
金额:
$7.33万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-05 至 2021-06-30
关键词:
Acidic RegionAcidsAmino AcidsAnionsAntibodiesBiologicalBiological AssayBiological ProcessBiologyCatalogingCatalogsCationsCell CycleCell MobilityCellsComplementComplexDataData AnalysesData SetDevelopmentDiseaseDissociationElectron TransportEnzymesEventFoundationsIn VitroIonsKnowledgeLabelMapsMass Spectrum AnalysisMetabolismMethodologyMethodsModificationNoisePeptidesPhosphotransferasesPost-Translational Protein ProcessingPreparationProcessProteinsProteomeProteomicsReactionReagentRegulationResearchSamplingSignal TransductionSignaling MoleculeSiteSpecificitySystemTechnologybasehigh throughput technologyinterestnovelphotoactivationprotein aminoacid sequence
中文摘要
项目总结
英文摘要
Project Summary
Post-translational modification (PTM) of proteins is a pervasive form of cell signaling that orchestrates numerous
processes, including metabolism, cell mobility, cell cycle, and differentiation. As a result, improper regulation of
PTMs is widely implicated in aberrant development and disease. Mechanistically, post-translational modification
provides a rapid and largely reversible means to modulate protein activity and transduce signals. Thus, the
proteome and its modifications represent a rich and informative experimental plane. Research that seeks to
understand its dynamics will doubtless advance our understanding of fundamental biology and disease. Mass
spectrometry (MS) is well-suited to proteomic analysis because it is highly sensitive, has the capacity to localize
PTMs to a single amino acid, and, unlike antibody-based methods, does not require a priori knowledge of protein
targets or post-translational modifications; indeed, MS has been used to catalog the complexity of various PTMs
with great detail. That said, two major challenges remain. First, the field of proteomics almost uniformly
relies on peptide cation analysis (i.e., positive electrospray). The consequence of this format is that acidic PTMs,
and all PTMs contained in acidic regions of the proteome, are often difficult, or impossible, to detect because
they do not ionize effectively under the standard low-pH conditions. We confront this problem by developing
high-pH separations methodology along with negative electron transfer dissociation (NETD). NETD allows for
the sequencing of peptide anions and should permit access to previously unobserved PTMs and portions of the
proteome. The second major challenge is how to convert large PTM datasets to biological information. To
counter this issue we propose a high-throughput technology, multiplexed assay for enzyme specificity (MAES),
that converts discovery PTM data to functional information by en masse substrate-to-enzyme mapping. Mapping
the enzymes responsible for a specific modification event is instructive because it places those modifications in
the context of signaling molecules that direct biological function. Many of the DBPs in the Center will establish
comprehensive lists of PTMs, which will serve as the foundation for further study. To provide direction for these
studies, targeted, yet scalable, assays are necessary to map the enzymes that regulate modification sites of
interest.
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依托单位:
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