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Review
. 2010 Dec;11(12):861-71.
doi: 10.1038/nrm3011.

The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition

Jaclyn R Gareau  1 , Christopher D Lima
Affiliations
Review

The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition

Jaclyn R Gareau et al. Nat Rev Mol Cell Biol. 2010 Dec.

Abstract

Proteins of the small ubiquitin-related modifier (SUMO) family are conjugated to proteins to regulate such cellular processes as nuclear transport, transcription, chromosome segregation and DNA repair. Recently, numerous insights into regulatory mechanisms of the SUMO modification pathway have emerged. Although SUMO-conjugating enzymes can discriminate between SUMO targets, many substrates possess characteristics that facilitate their modification. Other post-translational modifications also regulate SUMO conjugation, suggesting that SUMO signalling is integrated with other signal transduction pathways. A better understanding of SUMO regulatory mechanisms will lead to improved approaches for analysing the function of SUMO and substrate conjugation in distinct cellular pathways.

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Figures

Figure 1
Figure 1. The SUMO conjugation cycle
Small ubiquitin-related modifier (SUMO) undergoes processing by ubiquitin-like protein-specific proteases (Ulps) and sentrin-specific proteases (SENPs) to its mature form (step 1), revealing a carboxy-terminal Gly-Gly motif. SUMO is then adenylated by the SUMO-activating enzyme subunit 1 (SAE1)-ubiquitin-like activating enzyme subunit 2 (UBA2) E1 complex in an ATP·Mg2+-dependent reaction and transferred to the catalytic Cys of the UBA2 subunit (step 2). Following activation, SUMO is transferred to the catalytic Cys of the E2 conjugating enzyme, ubiquitin-like conjugating enzyme 9 (UBC9) (step 3). It can then catalyze conjugation to a substrate in an E3 ligase-independent manner through recognition of SUMO consensus motifs (ΨKXE) that contain a Lys acceptor residue (step 4). In addition, SUMO ligases can facilitate SUMO transfer through distinct mechanisms. The E3 ligase may coordinate the E2~SUMO thioester in an optimal conformation for catalysis without directly contacting the substrate, as is the case for Ran-binding protein 2 (RanBP2) (step 5). The Siz and PIAS (protein inhibitor of activated STAT) E3 ligases contact the E2 and SUMO through their SP-RING and Siz/PIAS carboxy-terminal domain (SP-CTD) domains, respectively (step 6). In both steps 5 and 6, substrate specificity is derived from the E2 enzyme. The Siz/PIAS family proteins also contain a PINIT domain that can contact the substrate, as is the case for the substrate proliferating cell nuclear antigen (PCNA), (step 7). Substrate specificity imparted by E3-substrate interactions are thought to be particularly important for directing conjugation to non-consensus Lys residues. Substrates modified by SUMO can contact SUMO-binding proteins through their SUMO-interacting motifs (SIMs) (step 8). Deconjugation is performed by Ulp and SENP proteases and free SUMO may be recycled for another round of conjugation (step 9).
Figure 2
Figure 2. SUMO consensus motifs and SUMO-interacting motifs
a | Amino acid sequence alignment of the canonical small ubiquitin-related modifier (SUMO) consensus motif, inverted consensus motif, hydrophobic cluster motif, phosphorylation-dependent SUMO motif (PDSM) and negatively charged amino acid-dependent SUMO motif (NDSM). Ψ represents a hydrophobic amino acid and K is the Lys modified by SUMO. b | Electrostatic potential surface representation of ubiquitin-like conjugating enzyme 9 (UBC9) adjacent to the Ran GTPase-activating protein 1 (RanGAP1) consensus motif (Protein Databank (PDB) code 2GRN). A model for the PDSM motif shown in stick representation was constructed by combining the RanGAP1 consensus motif with a phosphorylated peptide obtained from a complex between PIN1 and a phosphorylated RNA polymerase II carboxy-terminal domain peptide (PDB code 1F8A). The phosphorylated serine of the PDSM interacts with a basic patch on the surface of UBC9. Lys residues on UBC9 that are important for phosphate recognition are labeled. c | Sequence alignment of selected SUMO-interacting motifs (SIMs). Residues of the hydrophobic core sequence are highlighted in blue. Acidic residues and phosphorylated Ser residues are marked in pink and green, respectively. d | Electrostatic surface representation of human SUMO1 bound to a stick representation of the SIM of Ran-binding protein 2 internal repeat 1 (RanBP2 IR1; PDB code 1Z5S). SUMO1 and the Lys and Arg residues thought to be important for contacting phospho-SIMs and acidic residue flanking SIMs are labeled. Positive, apolar and acidic electrostatic potential on UBC9 and SUMO1 surfaces is indicated as blue, white and red, respectively. Molecular graphic representations of the structure were generated using PyMOL. PIAS, protein inhibitor of activated STAT; PML, promyelocytic leukemia protein; TDG, thymine DNA glycosylase; USP25, ubiquitin-specific protease 25.
Figure 3
Figure 3. Roles of SUMO-interacting motifs
a | A specific small ubiquitin-related modifier (SUMO)-interacting motif (SIM) on ubiquitin-specific protease 25 (USP25) results in its modification by SUMO2 and/or SUMO3. b | Phosphorylation of SIMs that contain adjacent Ser residues (phospho-SIMs) by casein kinase 2 (CK2) activates non-covalent interactions between SUMO and protein inhibitor of activated STAT 1 (PIAS1). c | SIMs present on SUMO-targeted ubiquitin ligases recognize SUMO chains on promyelocytic leukemia protein (PML). This results in ubiquitylation of Lys residues on PML by a ubiquitin E2 conjugation enzyme (Ub E2) and the ligase, RING finger protein 4 (RNF4), followed by proteasome-mediated degradation. d | A SUMO-like domain (SLD) present in the yeast DNA repair protein Rad60 is recognized by SIMs on the SUMO-targeted Slx8-RING finger protein (Rfp) ubiquitin E3 ligase complex, although the consequences of these interactions are unclear.
Figure 4
Figure 4. Phosphorylation and SUMO modification regulate transcription factors
a | Transcription factors, including nuclear factor-κB (NF-κB) inhibitor α (IκBα), are regulated through post-translation modifications. Phosphorylation of IκBα by the IκB kinase (IKK) outside a phosphorylation-dependent small ubiquitin-related modifier (SUMO) motif (PDSM) inhibits its SUMO modification by ubiquitin-like conjugating enzyme 9 (UBC9) and promotes modification by ubiquitin, targeting IκBα for degradation and releasing the transcription factor NF-κB to turn on target gene transcription. SUMO modification of IκBα in the absence of phosphorylation inhibits transcription by blocking IκBα turnover and release of NF-κB. b | Phosphorylation of the transcription factor myocyte-specific enhancer factor 2A (MEF2A) by cyclin-dependent kinase 5 (CDK5) within a PDSM enhances its modification by SUMO, inhibiting transcription and resulting in synapse maturation. Calcium signaling results in dephosphorylation by the calcium-dependent phosphatase calcineurin and acetylation of MEF2A by the histone acetyl transferases CREB-binding protein (CBP) and p300, converting it from a transcriptional repressor to a transcriptional activator and causing synapse disassembly.
Figure 5
Figure 5. Recruitment to PCNA by ubiquitin-like proteins
Post-translational modification of the processivity factor for eukaryotic DNA polymerases, proliferating cell nuclear antigen (PCNA), by ubiquitin-like modifiers results in the recruitment of specific proteins that otherwise display weak interactions with PCNA. In response to DNA damage, monoubiquitylation of PCNA by the yeast E2 conjugating enzyme Rad6 and the E3 ligase Rad18 recruits translesion polymerases and results in error-prone damage bypass. After monoubiquitylation, polyubiquitylation of PCNA by an E2 complex – comprising ubiquitin-conjugating enzyme 13 (Ubc13) and the ubiquitin-conjugating enzyme variant Mms2 – and the ubiquitin E3 ligase Rad5 results in error-free repair, although the specific factors recruited are not clear. PCNA is also modified by small ubiquitin-related modifier (SUMO) on Lys164 during S phase by the E2 enzyme ubiquitin-like conjugating enzyme 9 (Ubc9) and the SUMO E3 ligase Siz1, and on Lys127 by Ubc9, Siz1 and Siz2. This results in recruitment of the ATP-dependent DNA helicase Srs2 to inhibit recombination during replication.
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