Protection from Isopeptidase-Mediated Deconjugation Regulates Paralog-Selective Sumoylation of RanGAP1

• Published in: Molecular cell Vol. 33; no. 5; pp. 570 - 580
• Main Authors: Zhu, Shanshan, Goeres, Jacqueline, Sixt, Katherine M., Békés, Miklós, Zhang, Xiang-Dong, Salvesen, Guy S., Matunis, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-03-2009
• Subjects: 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; PROTEINS; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; RNA Interference; RNA, Small Interfering - metabolism; Small Ubiquitin-Related Modifier Proteins - chemistry; Small Ubiquitin-Related Modifier Proteins - metabolism; SUMO-1 Protein - metabolism; Time Factors; Transfection; Ubiquitin-Conjugating Enzymes - metabolism; PROTEINS
• ISSN: 1097-2765; 1097-4164
• 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.