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|3uip, resolution 2.29Å ()|
|Gene:||UBC9, UBCE9, UBE2I (Homo sapiens), OK/SW-cl.43, SMT3C, SMT3H3, SUMO1, UBL1 (Homo sapiens), KIAA1835, RANGAP1, SD (Homo sapiens), NUP358, RANBP2 (Homo sapiens)|
|Related:||1z5s, 3uio, 3uin|
Complex between human RanGAP1-SUMO1, UBC9 and the IR1 domain from RanBP2 containing IR2 Motif II
The RanBP2 nucleoporin contains an internal repeat domain (IR1-M-IR2) that catalyzes E3 ligase activity and forms a stable complex with SUMO-modified RanGAP1 and UBC9 at the nuclear pore complex. RanBP2 exhibits specificity for SUMO1 as RanGAP1-SUMO1/UBC9 forms a more stable complex with RanBP2 in comparison to RanGAP1-SUMO2 that results in greater protection of RanGAP-SUMO1 from proteases. The IR1-M-IR2 SUMO E3 ligase activity also shows a similar preference for SUMO1. We utilized deletions and domain swap constructs in protease protection assays and auto-modification assays to define RanBP2 domains responsible for RanGAP1-SUMO1 protection and SUMO1-specific E3 ligase activity. Our data suggest that elements in both IR1 and IR2 exhibit specificity for SUMO1. IR1 protects RanGAP1-SUMO1/UBC9 and functions as the primary E3 ligase of RanBP2, while IR2 retains the ability to interact with SUMO1 to promote SUMO1-specific E3 ligase activity. To determine the structural basis for SUMO1 specificity, a hybrid IR1 construct and IR1 were used to determine three new structures for complexes containing UBC9 with RanGAP1-SUMO1/2. These structures show more extensive contacts between SUMO, UBC9 and RanBP2 in complexes containing SUMO1 in comparison to SUMO2 and suggest that differences in SUMO specificity may be achieved through these subtle conformational differences.
Determinants of SUMO1 specificity, E3 ligase and SUMO-RanGAP1 binding activities of the nucleoporin RanBP2., Gareau JR, Reverter D, Lima CD, J Biol Chem. 2011 Dec 22. PMID:22194619
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[RBP2_HUMAN] Defects in RANBP2 are the cause of encephalopathy acute infection-induced type 3 (IIAE3) [MIM:608033]. A rapidly progressive encephalopathy manifesting in susceptibile individuals with seizures and coma. It can occur within days in otherwise healthy children after common viral infections such as influenza and parainfluenza, without evidence of viral infection of the brain or inflammatory cell infiltration. Brain T2-weighted magnetic resonance imaging reveals characteristic symmetric lesions present in the thalami, pons and brainstem. Note=Mutations in the RANBP2 gene predispose to IIAE3, but by themselves are insufficient to make the phenotype fully penetrant; additional genetic and environmental factors are required (PubMed:19118815). [SUMO1_HUMAN] Defects in SUMO1 are the cause of non-syndromic orofacial cleft type 10 (OFC10) [MIM:613705]; also called non-syndromic cleft lip with or without cleft palate 10. OFC10 is a birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. Note=A chromosomal aberation involving SUMO1 is the cause of OFC10. Translocation t(2;8)(q33.1;q24.3). The breakpoint occurred in the SUMO1 gene and resulted in haploinsufficiency confirmed by protein assays.
[RBP2_HUMAN] E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I. Involved in transport factor (Ran-GTP, karyopherin)-mediated protein import via the F-G repeat-containing domain which acts as a docking site for substrates. Could also have isomerase or chaperone activity and may bind RNA or DNA. Component of the nuclear export pathway. Specific docking site for the nuclear export factor exportin-1.    [UBC9_HUMAN] Accepts the ubiquitin-like proteins SUMO1, SUMO2, SUMO3 and SUMO4 from the UBLE1A-UBLE1B E1 complex and catalyzes their covalent attachment to other proteins with the help of an E3 ligase such as RANBP2 or CBX4. Can catalyze the formation of poly-SUMO chains. Necessary for sumoylation of FOXL2 and KAT5. Essential for nuclear architecture and chromosome segregation.       [RAGP1_HUMAN] GTPase activator for the nuclear Ras-related regulatory protein Ran, converting it to the putatively inactive GDP-bound state. [SUMO1_HUMAN] Ubiquitin-like protein that can be covalently attached to proteins as a monomer or a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by E3 ligases such as PIAS1-4, RANBP2 or CBX4. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Involved for instance in targeting RANGAP1 to the nuclear pore complex protein RANBP2. Polymeric SUMO1 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins. May also regulate a network of genes involved in palate development.   
About this Structure
- Gareau JR, Reverter D, Lima CD. Determinants of SUMO1 specificity, E3 ligase and SUMO-RanGAP1 binding activities of the nucleoporin RanBP2. J Biol Chem. 2011 Dec 22. PMID:22194619 doi:10.1074/jbc.M111.321141
- ↑ Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, Anderson J, Bassuk AG, Bye AM, Childs AM, Clarke A, Crow YJ, Di Rocco M, Dohna-Schwake C, Dueckers G, Fasano AE, Gika AD, Gionnis D, Gorman MP, Grattan-Smith PJ, Hackenberg A, Kuster A, Lentschig MG, Lopez-Laso E, Marco EJ, Mastroyianni S, Perrier J, Schmitt-Mechelke T, Servidei S, Skardoutsou A, Uldall P, van der Knaap MS, Goglin KC, Tefft DL, Aubin C, de Jager P, Hafler D, Warman ML. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet. 2009 Jan;84(1):44-51. doi: 10.1016/j.ajhg.2008.12.009. PMID:19118815 doi:10.1016/j.ajhg.2008.12.009
- ↑ Alkuraya FS, Saadi I, Lund JJ, Turbe-Doan A, Morton CC, Maas RL. SUMO1 haploinsufficiency leads to cleft lip and palate. Science. 2006 Sep 22;313(5794):1751. PMID:16990542 doi:10.1126/science.1128406
- ↑ Pichler A, Gast A, Seeler JS, Dejean A, Melchior F. The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell. 2002 Jan 11;108(1):109-20. PMID:11792325
- ↑ Kirsh O, Seeler JS, Pichler A, Gast A, Muller S, Miska E, Mathieu M, Harel-Bellan A, Kouzarides T, Melchior F, Dejean A. The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J. 2002 Jun 3;21(11):2682-91. PMID:12032081 doi:10.1093/emboj/21.11.2682
- ↑ Pichler A, Knipscheer P, Saitoh H, Sixma TK, Melchior F. The RanBP2 SUMO E3 ligase is neither HECT- nor RING-type. Nat Struct Mol Biol. 2004 Oct;11(10):984-91. Epub 2004 Sep 19. PMID:15378033 doi:10.1038/nsmb834
- ↑ Reverter D, Lima CD. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. Nature. 2005 Jun 2;435(7042):687-92. PMID:15931224 doi:10.1038/nature03588
- ↑ Yasugi T, Howley PM. Identification of the structural and functional human homolog of the yeast ubiquitin conjugating enzyme UBC9. Nucleic Acids Res. 1996 Jun 1;24(11):2005-10. PMID:8668529
- ↑ Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH, Hay RT. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem. 2001 Sep 21;276(38):35368-74. Epub 2001 Jul 12. PMID:11451954 doi:10.1074/jbc.M104214200
- ↑ Kim YE, Kim DY, Lee JM, Kim ST, Han TH, Ahn JH. Requirement of the coiled-coil domain of PML-RARalpha oncoprotein for localization, sumoylation, and inhibition of monocyte differentiation. Biochem Biophys Res Commun. 2005 May 13;330(3):746-54. PMID:15809060 doi:10.1016/j.bbrc.2005.03.052
- ↑ Kuo FT, Bentsi-Barnes IK, Barlow GM, Bae J, Pisarska MD. Sumoylation of forkhead L2 by Ubc9 is required for its activity as a transcriptional repressor of the Steroidogenic Acute Regulatory gene. Cell Signal. 2009 Dec;21(12):1935-44. doi: 10.1016/j.cellsig.2009.09.001. Epub, 2009 Sep 8. PMID:19744555 doi:10.1016/j.cellsig.2009.09.001
- ↑ Figueroa-Romero C, Iniguez-Lluhi JA, Stadler J, Chang CR, Arnoult D, Keller PJ, Hong Y, Blackstone C, Feldman EL. SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J. 2009 Nov;23(11):3917-27. doi: 10.1096/fj.09-136630. Epub 2009 Jul 28. PMID:19638400 doi:10.1096/fj.09-136630
- ↑ Capili AD, Lima CD. Structure and analysis of a complex between SUMO and Ubc9 illustrates features of a conserved E2-Ubl interaction. J Mol Biol. 2007 Jun 8;369(3):608-18. Epub 2007 Apr 6. PMID:17466333 doi:10.1016/j.jmb.2007.04.006
- ↑ Sekiyama N, Arita K, Ikeda Y, Hashiguchi K, Ariyoshi M, Tochio H, Saitoh H, Shirakawa M. Structural basis for regulation of poly-SUMO chain by a SUMO-like domain of Nip45. Proteins. 2009 Dec 4. PMID:20077568 doi:10.1002/prot.22667
- ↑ Mahajan R, Delphin C, Guan T, Gerace L, Melchior F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell. 1997 Jan 10;88(1):97-107. PMID:9019411
- ↑ Kamitani T, Nguyen HP, Yeh ET. Preferential modification of nuclear proteins by a novel ubiquitin-like molecule. J Biol Chem. 1997 May 30;272(22):14001-4. PMID:9162015
- ↑ Meulmeester E, Kunze M, Hsiao HH, Urlaub H, Melchior F. Mechanism and consequences for paralog-specific sumoylation of ubiquitin-specific protease 25. Mol Cell. 2008 Jun 6;30(5):610-9. doi: 10.1016/j.molcel.2008.03.021. PMID:18538659 doi:10.1016/j.molcel.2008.03.021
- ↑ Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008 May;10(5):538-46. doi: 10.1038/ncb1716. Epub 2008 Apr 13. PMID:18408734 doi:10.1038/ncb1716