Identification of biochemically distinct properties of the small ubiquitin-related modifier (SUMO) conjugation pathway in Plasmodium falciparum

J Biol Chem. 2013 Sep 27;288(39):27724-36. doi: 10.1074/jbc.M113.498410. Epub 2013 Aug 13.


Small ubiquitin-related modifiers (SUMOs) are post-translationally conjugated to other proteins and are thereby essential regulators of a wide range of cellular processes. Sumoylation, and enzymes of the sumoylation pathway, are conserved in the malaria causing parasite, Plasmodium falciparum. However, the specific functions of sumoylation in P. falciparum, and the degree of functional conservation between enzymes of the human and P. falciparum sumoylation pathways, have not been characterized. Here, we demonstrate that sumoylation levels peak during midstages of the intra-erythrocyte developmental cycle, concomitant with hemoglobin consumption and elevated oxidative stress. In vitro studies revealed that P. falciparum E1- and E2-conjugating enzymes interact effectively to recognize and modify RanGAP1, a model mammalian SUMO substrate. However, in heterologous reactions, P. falciparum E1 and E2 enzymes failed to interact with cognate human E2 and E1 partners, respectively, to modify RanGAP1. Structural analysis, binding studies, and functional assays revealed divergent amino acid residues within the E1-E2 binding interface that define organism-specific enzyme interactions. Our studies identify sumoylation as a potentially important regulator of oxidative stress response during the P. falciparum intra-erythrocyte developmental cycle, and define E1 and E2 interactions as a promising target for development of parasite-specific inhibitors of sumoylation and parasite replication.

Keywords: Crystal Structure; Malaria; Plasmodium; Sumo; Sumoylation; Ubiquitin-conjugating Enzyme (Ubc).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Erythrocytes / metabolism
  • Gene Expression Regulation
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Microscopy, Fluorescence
  • Molecular Conformation
  • Molecular Sequence Data
  • Oxidative Stress
  • Plasmodium falciparum / metabolism*
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protozoan Proteins / metabolism*
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Sumoylation
  • Ubiquitin / metabolism
  • Ubiquitin-Activating Enzymes / metabolism*
  • Ubiquitin-Conjugating Enzymes / metabolism*


  • Protozoan Proteins
  • Recombinant Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • UBA2 protein, human
  • Ubiquitin
  • Green Fluorescent Proteins
  • Ubiquitin-Conjugating Enzymes
  • SAE1 protein, human
  • Ubiquitin-Activating Enzymes
  • ubiquitin-conjugating enzyme UBC9

Associated data

  • PDB/4JUE
  • PDB/4M1N