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Global profiling of proteolysis during rupture of plasmodium falciparum from the host erythrocyte

Academic Article
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Overview

related to degree

  • Simon, Gabriel, Ph.D. in Chemistry, Scripps Research 2004 - 2009

authors

  • Bowyer, P. W.
  • Simon, Gabriel
  • Cravatt, Benjamin
  • Bogyo, M.

publication date

  • May 2011

journal

  • Molecular & Cellular Proteomics  Journal

abstract

  • The obligate intracellular parasite pathogen Plasmodium falciparum is the causative agent of malaria, a disease that results in nearly one million deaths per year. A key step in disease pathology in the human host is the parasite-mediated rupture of red blood cells, a process that requires extensive proteolysis of a number of host and parasite proteins. However, only a relatively small number of specific proteolytic processing events have been characterized. Here we describe the application of the Protein Topography and Migration Analysis Platform (PROTOMAP) (Dix, M. M., Simon, G. M., and Cravatt, B. F. (2008) Global mapping of the topography and magnitude of proteolytic events in apoptosis. Cell 134, 679-691; Simon, G. M., Dix, M. M., and Cravatt, B. F. (2009) Comparative assessment of large-scale proteomic studies of apoptotic proteolysis. ACS Chem. Biol. 4, 401-408) technology to globally profile proteolytic events occurring over the last 6-8 h of the intraerythrocytic cycle of P. falciparum. Using this method, we were able to generate peptographs for a large number of proteins at 6 h prior to rupture as well as at the point of rupture and in purified merozoites after exit from the host cell. These peptographs allowed assessment of proteolytic processing as well as changes in both protein localization and overall stage-specific expression of a large number of parasite proteins. Furthermore, by using a highly selective inhibitor of the cysteine protease dipeptidyl aminopeptidase 3 (DPAP3) that has been shown to be a key regulator of host cell rupture, we were able to identify specific substrates whose processing may be of particular importance to the process of host cell rupture. These results provide the first global map of the proteolytic processing events that take place as the human malarial parasite extracts itself from the host red blood cell. These data also provide insight into the biochemical events that take place during host cell rupture and are likely to be valuable for the study of proteases that could potentially be targeted for therapeutic gain.

subject areas

  • Amino Acid Sequence
  • Cell Culture Techniques
  • Cysteine Proteinase Inhibitors
  • Cytoplasm
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • Erythrocytes
  • Host-Parasite Interactions
  • Humans
  • Malaria, Falciparum
  • Membrane Proteins
  • Merozoites
  • Molecular Weight
  • Peptide Fragments
  • Plasmodium falciparum
  • Protein Processing, Post-Translational
  • Proteome
  • Software
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Identity

PubMed Central ID

  • PMC3098579

International Standard Serial Number (ISSN)

  • 1535-9476

Digital Object Identifier (DOI)

  • 10.1074/mcp.M110.001636

PubMed ID

  • 20943600
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Additional Document Info

start page

  • M110.001636

volume

  • 10

issue

  • 5

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