Allosteric activation of SENP1 by SUMO1 β-grasp domain involves a dock-and-coalesce mechanism

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Abstract

Small ubiquitin-related modifiers (SUMOs) are conjugated to proteins to regulate a variety of cellular processes. SENPs are cysteine proteases with a catalytic center located within a channel between two subdomains that catalyzes SUMO C-terminal cleavage for processing of SUMO precursors and de-SUMOylation of target proteins. The β-grasp domain of SUMOs binds to an exosite cleft, and allosterically activates SENPs via an unknown mechanism. Our molecular dynamics simulations showed that binding of the β-grasp domain induces significant conformational and dynamic changes in SENP1, including widening of the exosite cleft and quenching of nanosecond dynamics in all but a distal region. A dock-and-coalesce mechanism emerges for SENP-catalyzed SUMO cleavage: the wedging of the β-grasp domain enables the docking of the proximal portion of the C-terminus and the strengthened cross-channel motional coupling initiates inter-subdomain correlated motions to allow for the distal portion to coalesce around the catalytic center.

DOI: http://dx.doi.org/10.7554/eLife.18249.001

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Most cited references 27

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Protein modification by SUMO.

Erica Johnson (2004)

Small ubiquitin-related modifier (SUMO) family proteins function by becoming covalently attached to other proteins as post-translational modifications. SUMO modifies many proteins that participate in diverse cellular processes, including transcriptional regulation, nuclear transport, maintenance of genome integrity, and signal transduction. Reversible attachment of SUMO is controlled by an enzyme pathway that is analogous to the ubiquitin pathway. The functional consequences of SUMO attachment vary greatly from substrate to substrate, and in many cases are not understood at the molecular level. Frequently SUMO alters interactions of substrates with other proteins or with DNA, but SUMO can also act by blocking ubiquitin attachment sites. An unusual feature of SUMO modification is that, for most substrates, only a small fraction of the substrate is sumoylated at any given time. This review discusses our current understanding of how SUMO conjugation is controlled, as well as the roles of SUMO in a number of biological processes.

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Dynamical networks in tRNA:protein complexes.

Anurag Sethi, John Eargle, Alexis A. Black … (2009)

Community network analysis derived from molecular dynamics simulations is used to identify and compare the signaling pathways in a bacterial glutamyl-tRNA synthetase (GluRS):tRNA(Glu) and an archaeal leucyl-tRNA synthetase (LeuRS):tRNA(Leu) complex. Although the 2 class I synthetases have remarkably different interactions with their cognate tRNAs, the allosteric networks for charging tRNA with the correct amino acid display considerable similarities. A dynamic contact map defines the edges connecting nodes (amino acids and nucleotides) in the physical network whose overall topology is presented as a network of communities, local substructures that are highly intraconnected, but loosely interconnected. Whereas nodes within a single community can communicate through many alternate pathways, the communication between monomers in different communities has to take place through a smaller number of critical edges or interactions. Consistent with this analysis, there are a large number of suboptimal paths that can be used for communication between the identity elements on the tRNAs and the catalytic site in the aaRS:tRNA complexes. Residues and nucleotides in the majority of pathways for intercommunity signal transmission are evolutionarily conserved and are predicted to be important for allosteric signaling. The same monomers are also found in a majority of the suboptimal paths. Modifying these residues or nucleotides has a large effect on the communication pathways in the protein:RNA complex consistent with kinetic data.

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SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia.

Jinke Cheng, Xunlei Kang, Sui Zhang … (2007)

SUMOylation is a dynamic process, catalyzed by SUMO-specific ligases and reversed by Sentrin/SUMO-specific proteases (SENPs). The physiologic consequences of SUMOylation and deSUMOylation are not fully understood. Here we investigate the phenotypes of mice lacking SENP1 and find that SENP1(-/-) embryos show severe fetal anemia stemming from deficient erythropoietin (Epo) production and die midgestation. We determine that SENP1 controls Epo production by regulating the stability of hypoxia-inducible factor 1alpha (HIF1alpha) during hypoxia. Hypoxia induces SUMOylation of HIF1alpha, which promotes its binding to a ubiquitin ligase, von Hippel-Lindau (VHL) protein, through a proline hydroxylation-independent mechanism, leading to its ubiquitination and degradation. In SENP1(-/-) MEFs, hypoxia-induced transcription of HIF1alpha-dependent genes such as vascular endothelial growth factor (VEGF) and glucose transporter 1 (Glut-1) is markedly reduced. These results show that SENP1 plays a key role in the regulation of the hypoxic response through regulation of HIF1alpha stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.

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Author and article information

Contributors

Volker Dötsch

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 31 August 2016

Publication date Collection: 2016

Volume: 5

Electronic Location Identifier: e18249

Affiliations

[1 ]deptHenan Engineering Research Center of Chiral Hydroxyl Pharmaceuticals, School of Chemistry and Chemical Engineering , Henan Normal University , Xinxiang, China

[2 ]deptDepartment of Physics , Institute of Molecular Biophysics, Florida State University , Tallahassee, United States

[3]Goethe University , Germany

[4]Goethe University , Germany

Author notes

hzhou4@ 123456fsu.edu

Author information

Huan-Xiang Zhou http://orcid.org/0000-0001-9020-0302

Article

Publisher ID: 18249

DOI: 10.7554/eLife.18249

PMC ID: 5030089

PubMed ID: 27576863

SO-VID: d30d3c91-8b94-4a35-8d14-8fd00d2fbcd3

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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 27 May 2016

Date accepted : 29 August 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: GM058187

Award Recipient : Huan-Xiang Zhou

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: GM118091

Award Recipient : Huan-Xiang Zhou

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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Author impact statement Simulations of molecular dynamics suggest how the binding of the β-grasp domain of SUMO1 induces conformational and dynamic effects to activate SENP1.

ScienceOpen disciplines: Life sciences

Keywords: allosteric activation,sumoylation,protein dynamics,dock-and-coalesce,human

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ScienceOpen disciplines: Life sciences

Keywords: allosteric activation, sumoylation, protein dynamics, dock-and-coalesce, human

Allosteric activation of SENP1 by SUMO1 β-grasp domain involves a dock-and-coalesce mechanism

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Most cited references 27

Protein modification by SUMO.

Dynamical networks in tRNA:protein complexes.

SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia.

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