N-Terminal Protein Tails Act as Aggregation Protective Entropic Bristles: The SUMO Case

Graña-Montes, Ricardo; Marinelli, Patrizia; Reverter, David; Ventura, Salvador

doi:10.1021/bm401776z

Cited by 35 publications

(35 citation statements)

References 49 publications

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“…It may also affect the aggregation properties of target proteins. An alternative mechanism that has been proposed is that SUMO directly affects inter- or intramolecular interactions of target proteins (Graña-Montes et al, 2014; Sabate et al, 2012). As mentioned above, our bioinformatics analysis has not as yet located a putative SUMO-interacting motif in the protein sequence of CPEB3, thereby excluding a direct interaction of SUMO and CPEB3.…”

Section: Discussionmentioning

confidence: 99%

SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3

Drisaldi¹,

Colnaghi²,

Fioriti³

et al. 2015

Cell Reports

109

140

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Summary Protein synthesis is crucial for the maintenance of long-term-memory-related synaptic plasticity. The prion-like cytoplasmic polyadenylation element-binding protein 3 (CPEB3) regulates the translation of several mRNAs important for long-term synaptic plasticity in the hippocampus. Here, we provide evidence that the prion-like aggregation and activity of CPEB3 is controlled by SUMOylation. In the basal state, CPEB3 is a repressor and is soluble. Under these circumstances, CPEB3 is SUMOylated in hippocampal neurons both in vitro and in vivo. Following neuronal stimulation, CPEB3 is converted into an active form that promotes the translation of target mRNAs, and this is associated with a decrease of SUMOylation and an increase of aggregation. A chimeric CPEB3 protein fused to SUMO cannot form aggregates and cannot activate the translation of target mRNAs. These findings suggest a model whereby SUMO regulates translation of mRNAs and structural synaptic plasticity by modulating the aggregation of the prion-like protein CPEB3.

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Section: Discussionmentioning

confidence: 99%

SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3

Drisaldi¹,

Colnaghi²,

Fioriti³

et al. 2015

Cell Reports

109

140

View full text Add to dashboard Cite

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“…Aggregation constraints the evolution of proteins and accordingly nature have evolved different strategies to minimize protein aggregation in sequences and structures. Essentially, mutations that result in an increase in aggregation propensity tend to be purged out from the population, especially when they occur in a disordered context, since they are exposed to solvent, being this the reason that intrinsically disordered protein segments are in general, very soluble ( Santner et al, 2012 ; Uversky, 2013 , 2015 ; Graña-Montes et al, 2014 ). In this context, the inherent amyloid potential of Rho cPrD strongly suggests that this protein segment, and the surrounding predicted PrD, are conserved because they serve functional purposes in C. botulinum , in agreement with the general view that PrDs are important for protein–protein interactions and provide the flexibility required to self-organizing macromolecular assemblies in living cells ( Malinovska et al, 2013 ; Iglesias et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

The Rho Termination Factor of Clostridium botulinum Contains a Prion-Like Domain with a Highly Amyloidogenic Core

2016

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Prion-like proteins can switch between a soluble intrinsically disordered conformation and a highly ordered amyloid assembly. This conformational promiscuity is encoded in specific sequence regions, known as prion domains (PrDs). Prions are best known as the causative factors of neurological diseases in mammals. However, bioinformatics analyses reveal that proteins bearing PrDs are present in all kingdoms of life, including bacteria, thus supporting the idea that they serve conserved beneficial cellular functions. Despite the proportion of predicted prion-like proteins in bacterial proteomes is generally low, pathogenic species seem to have a higher prionic load, suggesting that these malleable proteins may favor pathogenic traits. In the present work, we performed a stringent computational analysis of the Clostridium botulinum pathogen proteome in the search for prion-like proteins. A total of 54 candidates were predicted for this anaerobic bacterium, including the transcription termination Rho factor. This RNA-binding protein has been shown to play a crucial role in bacterial adaptation to changing environments. We show here that the predicted disordered PrD domain of this RNA-binding protein contains an inner, highly polar, asparagine-rich short sequence able to spontaneously self-assemble into amyloid-like structures, bearing thus the potential to induce a Rho factor conformational switch that might rewire gene expression in response to environmental conditions.

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“…We displayed an N-terminally truncated SUMO2 (herein referred to S2.WT) that lacks the first 14 unstructured residues (⌬N-14) including the primary site of SUMO chain formation (14). It was previously shown that the deletion of the unstructured N-terminal residues does not affect overall stability of SUMO2 (29). S2vs derived from such a library that additionally lack the C-terminal di-Gly motif (⌬GG) cannot be activated by the E1 complex or become a part of SUMO2/3 chains when expressed in cells.…”

Section: Library Design and Selection Of High Affinity Ubc9-binding Smentioning

confidence: 99%

Site-specific inhibition of the small ubiquitin-like modifier (SUMO)-conjugating enzyme Ubc9 selectively impairs SUMO chain formation

Wiechmann

Gärtner

Kniss

et al. 2017

Journal of Biological Chemistry

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Posttranslational modifications by small ubiquitin-like modifiers (SUMOs) regulate many cellular processes, including genome integrity, gene expression, and ribosome biogenesis. The E2-conjugating enzyme Ubc9 catalyzes the conjugation of SUMOs to ϵ-amino groups of lysine residues in target proteins. Attachment of SUMO moieties to internal lysines in Ubc9 itself can further lead to the formation of polymeric SUMO chains. Mono- and poly-SUMOylations of target proteins provide docking sites for distinct adapter and effector proteins important for regulating discrete SUMO-regulated pathways. However, molecular tools to dissect pathways depending on either mono- or poly-SUMOylation are largely missing. Using a protein-engineering approach, we generated high-affinity SUMO2 variants by phage display that bind the back side binding site of Ubc9 and function as SUMO-based Ubc9 inhibitors (SUBINs). Importantly, we found that distinct SUBINs primarily inhibit poly-SUMO chain formation, whereas mono-SUMOylation was not impaired. Proof-of-principle experiments demonstrated that in a cellular context, SUBINs largely prevent heat shock-triggered poly-SUMOylation. Moreover, SUBINs abrogated arsenic-induced degradation of promyelocytic leukemia protein. We propose that the availability of the new chain-selective SUMO inhibitors reported here will enable a thorough investigation of poly-SUMO-mediated cellular processes, such as DNA damage responses and cell cycle progression.

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N-Terminal Protein Tails Act as Aggregation Protective Entropic Bristles: The SUMO Case

Cited by 35 publications

References 49 publications

SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3

SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3

The Rho Termination Factor of Clostridium botulinum Contains a Prion-Like Domain with a Highly Amyloidogenic Core

Site-specific inhibition of the small ubiquitin-like modifier (SUMO)-conjugating enzyme Ubc9 selectively impairs SUMO chain formation

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