A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation

Owerbach, David; McKay, E.; Yeh, Edward T.H.; Gabbay, Kenneth H.; Bohren, Kurt M.

doi:10.1016/j.bbrc.2005.09.090

Cited by 213 publications

(151 citation statements)

References 24 publications

Supporting

Mentioning

150

Contrasting

Unclassified

Order By: Relevance

“…Mammalian genomes contain four SUMO genes, encoding SUMO1, SUMO2, SUMO3 (7,8), and SUMO4, of which SUMO4 is poorly characterized (9). SUMO2 and SUMO3 are almost identical, whereas SUMO1 is 50% homologous to SUMO2 and SUMO3.…”

mentioning

confidence: 99%

In vivo localization and identification of SUMOylated proteins in the brain of His ₆ -HA-SUMO1 knock-in mice

Tirard

Hsiao

Nikolov

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

125

View full text Add to dashboard Cite

SUMOylation, an essential posttranslational protein modification, is involved in many eukaryotic cellular signaling pathways. The identification of SUMOylated proteins is difficult, because SUMOylation sites in proteins are hard to predict, SUMOylated protein states are transient in vivo and labile in vitro, only a small substrate fraction is SUMOylated in vivo, and identification tools for natively SUMOylated proteins are rare. To solve these problems, we generated knock-in mice expressing His 6 -HA-SUMO1. By anti-HA immunostaining, we show that SUMO1 conjugates in neurons are only detectable in nuclei and annulate lamellae. By anti-HA affinity purification, we identified several hundred candidate SUMO1 substrates, of which we validated Smchd1, Ctip2, TIF1γ, and Zbtb20 as novel substrates. The knock-in mouse represents an excellent mammalian model for studies on SUMO1 localization and screens for SUMO1 conjugates in vivo.synapse | affinity purification S UMOylation is a conserved posttranslational protein modification in eukaryotes, akin to ubiquitylation, and can affect the localization, interactions, function, or stability of substrates (1). SUMOylation processes participate in many cellular signaling pathways, where they intersect with other posttranslational regulatory processes such as phosphorylation, ubiquitylation, or acetylation. Consequently, many cellular processes, from nuclear transport to neuronal synaptic transmission, are controlled by SUMOylation (2), and key SUMOylation substrates or altered SUMOylation are involved in many diseases, from cancer to neurological disorders (3).Reflecting the prominent nuclear role of SUMOylation, most known SUMOylation substrates are nuclear proteins (1, 2). However, SUMOylation appears to play a much more pervasive regulatory role in cells; recent studies have shown SUMOylation of ion channels, membrane-bound receptors, solute carriers, and mitochondrial or neuronal scaffolding and signaling proteins (4-6), leading to the notion that SUMOylation is a core regulatory process in all cellular subcompartments. This triggered substantial activities to develop tools for the discovery and validation of SUMOylation substrates in cells, which has proven difficult.Mammalian genomes contain four SUMO genes, encoding SUMO1, SUMO2, SUMO3 (7, 8), and SUMO4, of which SUMO4 is poorly characterized (9). SUMO2 and SUMO3 are almost identical, whereas SUMO1 is 50% homologous to SUMO2 and SUMO3. The 3D structure of SUMOs is similar to that of ubiquitin (10), and like ubiquitylation, SUMOylation involves an E1 activating enzyme, E2 conjugating enzymes, and E3 ligases (1,2,7,8).SUMOs are conjugated to lysine residues, often within a ϕKxD/E motif (ϕ, hydrophobic residue; x, any amino acid) (1), but in general SUMO acceptor lysines cannot be predicted, which prevents the identification of SUMO substrates by bioinformatics (1). Further, SUMOylated states of proteins are transient in vivo and labile in vitro because of isopeptidases that revert SUMOylation (1), and usually only a small f...

show abstract

mentioning

confidence: 99%

In vivo localization and identification of SUMOylated proteins in the brain of His ₆ -HA-SUMO1 knock-in mice

Tirard

Hsiao

Nikolov

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

125

View full text Add to dashboard Cite

show abstract

“…SUMO4 does not seem to participate in the formation of SUMO conjugates in vivo (6). After maturation of their C-terminal tail, SUMO2 and SUMO3 are 95% identical (thus referred as SUMO2/3 in the text), whereas SUMO1 shares only 43% identity to SUMO2 or SUMO3.…”

mentioning

confidence: 99%

Swapping Small Ubiquitin-like Modifier (SUMO) Isoform Specificity of SUMO Proteases SENP6 and SENP7

Alegre¹,

Reverter

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The SENP/ULP family of SUMO proteases display different cleavage preference for SUMO isoforms. Results: Insights into the structural determinants for the preference of SENP6 and SENP7 for the SUMO2/3 isoform. Conclusion: A novel interface between SENP6 or SENP7 and SUMO determines the SUMO isoform preference. Significance: This may be the first time that the cleavage preference between SUMO1 and SUMO2/3 was swapped by single point mutagenesis.

show abstract

“…A more recently identified gene encodes a fourth isoform very similar to SUMO2/3 (31). This form harbors a Pro residue at position 90 that prevents initial processing by known SUMO protease enzymes and subsequent conjugation (32). Whether this member functions through non-covalent interactions only remains to be determined.…”

mentioning

confidence: 99%

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Mukherjee¹,

Thomas

Dadgar

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The neurodegenerative disorder spinal and bulbar muscular atrophy or Kennedy disease is caused by a CAG trinucleotide repeat expansion within the androgen receptor (AR) gene. The resulting expanded polyglutamine tract in the N-terminal region of the receptor renders AR prone to ligand-dependent misfolding and formation of oligomers and aggregates that are linked to neuronal toxicity. How AR misfolding is influenced by post-translational modifications, however, is poorly understood. AR is a target of SUMOylation, and this modification inhibits AR activity in a promoter context-dependent manner. SUMOylation is up-regulated in response to multiple forms of cellular stress and may therefore play an important cytoprotective role. Consistent with this view, we find that gratuitous enhancement of overall SUMOylation significantly reduced the formation of polyglutamine-expanded AR aggregates without affecting the levels of the receptor. Remarkably, this effect requires SUMOylation of AR itself because it depends on intact AR SUMOylation sites. Functional analyses, however, indicate that the protective effects of enhanced AR SUMOylation are not due to alterations in AR transcriptional activity because a branched protein structure in the appropriate context of the N-terminal region of AR is necessary to antagonize aggregation but not for inhibiting AR transactivation. Remarkably, small ubiquitin-like modifier (SUMO) attenuates AR aggregation through a unique mechanism that does not depend on critical features essential for its interaction with canonical SUMO binding motifs. Our findings therefore reveal a novel function of SUMOylation and suggest that approaches that enhance AR SUMOylation may be of clinical use in polyglutamine expansion diseases.Spinal and bulbar muscular atrophy (SBMA), 2 or Kennedy disease, is an inherited degenerative disorder of lower motor neurons (1, 2). SBMA is characterized by muscle cramps and fasciculations followed by progressive weakness and atrophy of the proximal limb and bulbar muscles (3-5). The causative genetic alteration is an expansion in the length of a CAG trinucleotide repeat within the coding sequence of the androgen receptor (AR) gene, leading to an expanded polyglutamine tract in the N-terminal transcriptional regulatory domain of the receptor. A similar expansion within the coding sequence of a set of additional genes is responsible for other members of the polyglutamine class of protein folding diseases (6, 7), which include Huntington disease, several autosomal dominant spinocerebellar ataxias (SCAs) (8), and dentatorubral-pallidoluysian atrophy (9, 10).The length of the CAG repeat within AR is correlated to the severity of SBMA. Although the normal repeat length is highly polymorphic and ranges between 9 and 36 copies, overt disease is associated with lengths in the range of 38 -62 repeats. The presence of an expanded polyglutamine tract within AR renders the protein prone to hormone-dependent misfolding, oligomerization, and aggregation and to the formation of microscopica...

show abstract

A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation

Cited by 213 publications

References 24 publications

In vivo localization and identification of SUMOylated proteins in the brain of His ₆ -HA-SUMO1 knock-in mice

In vivo localization and identification of SUMOylated proteins in the brain of His ₆ -HA-SUMO1 knock-in mice

Swapping Small Ubiquitin-like Modifier (SUMO) Isoform Specificity of SUMO Proteases SENP6 and SENP7

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Contact Info

Product

Resources

About

A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation

Cited by 213 publications

References 24 publications

In vivo localization and identification of SUMOylated proteins in the brain of His 6 -HA-SUMO1 knock-in mice

In vivo localization and identification of SUMOylated proteins in the brain of His 6 -HA-SUMO1 knock-in mice

Swapping Small Ubiquitin-like Modifier (SUMO) Isoform Specificity of SUMO Proteases SENP6 and SENP7

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Contact Info

Product

Resources

About

In vivo localization and identification of SUMOylated proteins in the brain of His ₆ -HA-SUMO1 knock-in mice

In vivo localization and identification of SUMOylated proteins in the brain of His ₆ -HA-SUMO1 knock-in mice