Protection from isopeptidase-mediated deconjugation regulates paralog-selective sumoylation of RanGAP1

Mol Cell. 2009 Mar 13;33(5):570-80. doi: 10.1016/j.molcel.2009.02.008.


Vertebrates express three small ubiquitin-related modifiers (SUMO-1, SUMO-2, and SUMO-3) that are conjugated in part to unique subsets of proteins and, thereby, regulate distinct cellular processes. Mechanisms regulating paralog-selective sumoylation, however, remain poorly understood. Despite being equally well modified by SUMO-1 and SUMO-2 in vitro, RanGAP1 is selectively modified by SUMO-1 in vivo. We have found that this paralog-selective modification is determined at the level of deconjugation by isopeptidases. Our findings indicate that, relative to SUMO-2-modified RanGAP1, SUMO-1-modified RanGAP1 forms a more stable, higher affinity complex with the nucleoporin Nup358/RanBP2 that preferentially protects it from isopeptidases. By swapping residues in SUMO-1 and SUMO-2 responsible for Nup358/RanBP2 binding, or by manipulating isopeptidase expression levels, paralog-selective modification of RanGAP1 could be affected both in vitro and in vivo. Thus, protection from isopeptidases, through interactions with SUMO-binding proteins, represents an important mechanism defining paralog-selective sumoylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carbon-Nitrogen Lyases / genetics
  • Carbon-Nitrogen Lyases / metabolism*
  • Cell Line
  • Cysteine Endopeptidases / metabolism
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Chaperones / metabolism
  • Nuclear Pore Complex Proteins / metabolism
  • Protein Conformation
  • Protein Processing, Post-Translational*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / pharmacology
  • SUMO-1 Protein / metabolism
  • Small Ubiquitin-Related Modifier Proteins / chemistry
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Time Factors
  • Transfection
  • Ubiquitin-Conjugating Enzymes / metabolism


  • GTPase-Activating Proteins
  • Molecular Chaperones
  • Nuclear Pore Complex Proteins
  • RNA, Small Interfering
  • Rangap1 protein, mouse
  • Recombinant Fusion Proteins
  • SUMO-1 Protein
  • Small Ubiquitin-Related Modifier Proteins
  • ran-binding protein 2
  • Ubiquitin-Conjugating Enzymes
  • Cysteine Endopeptidases
  • Ulp1 protease
  • Carbon-Nitrogen Lyases
  • isopeptidase
  • ubiquitin-conjugating enzyme UBC9