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The Small Ubiquitin-like Modifiers: Established and emerging roles in diseases Mike Tatham Ron Hay lab Wellcome Trust Centre for Gene Regulation and Expression.

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Presentation on theme: "The Small Ubiquitin-like Modifiers: Established and emerging roles in diseases Mike Tatham Ron Hay lab Wellcome Trust Centre for Gene Regulation and Expression."— Presentation transcript:

1 The Small Ubiquitin-like Modifiers: Established and emerging roles in diseases Mike Tatham Ron Hay lab Wellcome Trust Centre for Gene Regulation and Expression University of Dundee ELRIG/SLAS Drug Discovery Manchester 2012

2 Phylogenetic relationship in the ubiquitin like modifier superfamily SUMO system is only found in Eukaryotes Yeasts, flies and worms only express a single SUMO Vertebrates express three paralogues SUMO-1, SUMO- 2, SUMO-3

3 ELRIG/SLAS Drug Discovery Manchester 2012 The SUMO conjugation system Ubiquitination Substrate Ubiquitin E1 (2) Ubiquitin E2 (~20) Ubiquitin E3 (hundreds) U U U U Substrate Ubiquitin Protease (~100) S S S S S SUMOylation SUMO E1 (1 – SAE1/2) SUMO E2 (1 – Ubc9) [SUMO E3 (10-20?)] SUMO Protease (8) Substrate SUMO system is only found in Eukaryotes Yeasts, flies and worms only express a single SUMO Vertebrates express three paralogues SUMO-1, SUMO- 2, SUMO-3 Like ubiquitin SUMOs are conjugated to protein substrates in a three step mechanism Most SUMO conjugation occurs within a consensus motif  KXE/D SUMO conjugation can occur independent of E3s SUMO-2 and SUMO-3 contain consensus motifs and can modify themselves to form polySUMO chains Deletion of yeast SUMO is lethal Deletion of Ubc9 in mice is lethal  KXE  KXD

4 Structural overview SUMO system is only found in Eukaryotes Yeasts, flies and worms only express a single SUMO Vertebrates express three paralogues SUMO-1, SUMO- 2, SUMO-3 Like ubiquitin SUMOs are conjugated to protein substrates in a three step mechanism Most SUMO conjugation occurs within a consensus motif  KXE/D SUMO conjugation can occur independent of E3s SUMO-2 and SUMO-3 contain consensus motifs and can modify themselves to form polySUMO chains Deletion of yeast SUMO is lethal Deletion of Ubc9 in mice is lethal SUMOs have low sequence homology to ubiquitin but high 3D structural similarity

5 ELRIG/SLAS Drug Discovery Manchester 2012 Cellular characteristics IB Ubiquitin IB SUMO-2/3 IB SUMO-1 U U U U Substrate U S S S S S S S Time (h) +MG Total extracts SUMO system is only found in Eukaryotes Yeasts, flies and worms only express a single SUMO Vertebrates express three paralogues SUMO-1, SUMO- 2, SUMO-3 Like ubiquitin SUMOs are conjugated to protein substrates in a three step mechanism Most SUMO conjugation occurs within a consensus motif  KXE/D SUMO conjugation can occur independent of E3s SUMO-2 and SUMO-3 contain consensus motifs and can modify themselves to form polySUMO chains Deletion of yeast SUMO is lethal Deletion of Ubc9 in mice is lethal SUMOs have low sequence homology to ubiquitin but high 3D structural similarity SUMOs are predominantly nuclear proteins SUMO-1 and SUMO-2/-3 have largely overlapping protein targets with some distinctions

6 ELRIG/SLAS Drug Discovery Manchester 2012 Molecular functions of SUMO S S S S S SUMOylation SUMO E1 (1 – SAE1/2) SUMO E2 (1 – Ubc9) [SUMO E3 (10-20?)] SUMO Protease (8) Substrate SUMO BP polySUMO BP Substrate S S S S S S S Subcellular localisation Enzymatic activity Complex formation Further modification Block modifications Altered function SUMO system is only found in Eukaryotes Yeasts, flies and worms only express a single SUMO Vertebrates express three paralogues SUMO-1, SUMO- 2, SUMO-3 Like ubiquitin SUMOs are conjugated to protein substrates in a three step mechanism Most SUMO conjugation occurs within a consensus motif  KXE/D SUMO conjugation can occur independent of E3s SUMO-2 and SUMO-3 contain consensus motifs and can modify themselves to form polySUMO chains Deletion of yeast SUMO is lethal Deletion of Ubc9 in mice is lethal SUMOs have low sequence homology to ubiquitin but high 3D structural similarity SUMOs are predominantly nuclear proteins SUMO-1 and SUMO-2/-3 have largely overlapping protein targets with some distinctions SUMO conjugation does not have a common effect on proteins, but has myriad of protein-specific consequences mediated by SUMO Interaction Motifs (SIMS)

7 Cellular functions of SUMO TAP-SUMO-2 cells Purify SUMO from cells Identify and quantify proteins by quantitative mass spectrometry-based proteomics Identified a total of ~900 SUMO substrates Number of SUMO substrates Year SubstrateTAGSUMO ELRIG/SLAS Drug Discovery Manchester 2012 ~10% of cellular proteins are modified by SUMO Golebiowski et al Sci Signal. 2009;2(72):ra24. Tatham et al Sci. Signal. 2011;4(178):rs4

8 SUMO ELRIG/SLAS Drug Discovery Manchester 2012 SUMO and human diseases Immunological disorders Centromere instability, and facial anomalies syndrome Autoimmune regulation Dermatomyositis Infectious diseases DNA viruses Protozoa Extra and Intra-cellular bacteria RNA viruses Circulatory Diseases Transient global and focal cerebral ischemia Familial dilated cardiomyopathy Congenital heart disease Obesity Others Rheumatoid arthritis Liver damage Cystic fibrosis Muscular dystrophy Heart failure Neurological disorders Multiple System Atrophy Alzheimer's disease Frontotemporal dementia Spinal and bulbar muscular atrophy Huntington's disease Amyotrophic lateral sclerosis Frontotemporal lobar degeneration Spinocerebellar ataxia type 1 Neuronal intranuclear inclusion disease Dementia with Lewy Bodies Parkinson's disease Amyotrophic lateral sclerosis Cancers Megakaryoblastic leukemia Squamous cell carcinoma Colon cancer Acute Promyelocytic leukaemia Breast cancer Ovarian cancer Multiple myeloma Melanoma Prostate cancer Atypical myeloproliferative disease Renal cell carcinoma

9 ELRIG/SLAS Drug Discovery Manchester 2012 SUMO and human diseases Types of evidence linking SUMO with diseases 1.Disease protein x is modified by SUMO which alters its function. 2.SUMO conjugation is altered in disease cells 3.SUMO is abnormally distributed within disease cells 4.Enzymes of the SUMO modification system are abnormally expressed in disease cells 5.SUMO system modulation alters the disease phenotype in model cells Alzheimer’s disease (Amyloid beta protein (derived from from APP)) (tau) Parkinson’s disease(  -synuclein, DJ-1) Prion disease(PrP) Polyglutamine diseasesHuntington’s (Huntingtin) Kennedy’s(Androgen Rec) Dentatorubro-pallidoluysian atrophy (Atrophin-1) Spinocerebellar ataxia (ATAXIN1, 7) Tauopathy (tau) Familial amyotrophic lateral sclerosis(SOD1) Fei et al. BBRC 347 (2006) Riley et al. JBC 280 (2005), Janer et al. Hum. Mol. Gen. 19 (2010) Li et al. PNAS 100 (2003) Juanes et al. JBC 284 (2009) Mukherjee et al. JBC (2009) Steffan et al. Science (2004) Dorval & Fraser. JBC 281 (2005), Shinbo et al. Cell. Death Diff. (2006) Dorval & Fraser. JBC 281 (2005) Terashima et al. Neuroreport. 13 (2002) Immunolabelling of NII in the hippocampal subiculum of patients with NIID. (Takahashi-Fujigasaki et al. Neuropathology and Applied Neurobiology (2006), 32, 92–100) Immunostaining of aggregates in glioma cell models for multiple system atrophy (MSA). (D.L. Pountney et al. Neuroscience Letters 381 (2005) 74–79)

10 SUMO BP ELRIG/SLAS Drug Discovery Manchester 2012 The SUMO-SIM interaction SUMO SIM peptide Q. How do we take advantage of the SUMO system therapeutically? A. It depends on what you want to do! S S S S S SUMO E1 (1 – SAE1/2) SUMO E2 (1 – Ubc9) [SUMO E3 (10-20?)] SUMO Protease (8) Substrate  KXE  KXD

11 Wimmer P, et al. J Virol Jan;86(2): To be or not to be specific: What can parasites tell us? Infectious diseases DNA viruses Protozoa Extra and Intra-cellular bacteria RNA viruses ELRIG/SLAS Drug Discovery Manchester 2012 Q. How do we take advantage of the SUMO system therapeutically? A. It depends on how specific you want to be!

12 SUMO ELRIG/SLAS Drug Discovery Manchester 2012 SUMO and human diseases Immunological disorders Centromere instability, and facial anomalies syndrome Autoimmune regulation Dermatomyositis Infectious diseases DNA viruses Protozoa Extra and Intra-cellular bacteria RNA viruses Circulatory Diseases Transient global and focal cerebral ischemia Familial dilated cardiomyopathy Congenital heart disease Obesity Others Rheumatoid arthritis Liver damage Cystic fibrosis Muscular dystrophy Heart failure Neurological disorders Multiple System Atrophy Alzheimer's disease Frontotemporal dementia Spinal and bulbar muscular atrophy Huntington's disease Amyotrophic lateral sclerosis Frontotemporal lobar degeneration Spinocerebellar ataxia type 1 Neuronal intranuclear inclusion disease Dementia with Lewy Bodies Parkinson's disease Amyotrophic lateral sclerosis Cancers Megakaryoblastic leukemia Squamous cell carcinoma Colon cancer Acute Promyelocytic leukaemia Breast cancer Ovarian cancer Multiple myeloma Melanoma Prostate cancer Atypical myeloproliferative disease Renal cell carcinoma

13 ELRIG/SLAS Drug Discovery Manchester 2012 Example of a successful drug therapy involving SUMO - APL De The et al J. Cell. Biol No Liu et al Curr. Op. Chem. Biol Acute Promyelocytic Leukaemia (APL) A rare condition driven by a chromosomal translocation resulting in the fusion of the PML and retinoic acid receptor  proteins (PML-RAR  ) Very malignant and charaterised by sudden hemorrhages and accumulation of promyelocytes in blood Retinoic acid and arsenic trioxide treatment induce differentiation of promyelocytes and clinical remission. PML-RAR  and PML are known to be SUMOylated and degraded in response to arsenic

14 ELRIG/SLAS Drug Discovery Manchester 2012 Example of a successful drug therapy involving SUMO - APL Ring Finger protein 4 (RNF4) aka SNURF Tatham et al Nat. Cell. Biol

15 ELRIG/SLAS Drug Discovery Manchester 2012 Example of a successful drug therapy involving SUMO - APL Tatham et al Nat. Cell. Biol

16 ELRIG/SLAS Drug Discovery Manchester 2012 A model for SUMO-dependent disease remission PML SUMO conjugation SUMO deconjugation Ubiquitin conjugation Ubiquitin deconjugation U PML S S S S S S S S S S U U U U U U U U ARSENIC RNF4 Tatham et al Nat. Cell. Biol

17 ELRIG/SLAS Drug Discovery Manchester 2012 The SUMO system as a therapeutic target - Summary SUMO is functionally highly pleiotropic affecting many important cellular pathways There is a range of evidence linking SUMO to significant human diseases. The precise role of SUMO in many diseases is not determined and so its potential as a therapeutic target is largely unclear The best approach to modulating SUMO function for individual disease therapy is unclear There is an academic and clinical argument for small molecule effectors of the SUMO system to help clarify these issues.

18 Ron Hay Filip Golebiowski (Glasgow) Ellis Jaffray Marie-Claude Geoffroy (Paris) Ivan Matic Amit Garg Jurgen Cox Matthias Mann ELRIG/SLAS Drug Discovery Manchester 2012 Acknowledgements


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