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Generation of specific inhibitors of SUMO-1- and SUMO-2/3-mediated protein-protein interactions using Affimer (Adhiron) technology.
- Source :
-
Science signaling [Sci Signal] 2017 Nov 14; Vol. 10 (505). Date of Electronic Publication: 2017 Nov 14. - Publication Year :
- 2017
-
Abstract
- Because protein-protein interactions underpin most biological processes, developing tools that target them to understand their function or to inform the development of therapeutics is an important task. SUMOylation is the posttranslational covalent attachment of proteins in the SUMO family (SUMO-1, SUMO-2, or SUMO-3), and it regulates numerous cellular pathways. SUMOylated proteins are recognized by proteins with SUMO-interaction motifs (SIMs) that facilitate noncovalent interactions with SUMO. We describe the use of the Affimer system of peptide display for the rapid isolation of synthetic binding proteins that inhibit SUMO-dependent protein-protein interactions mediated by SIMs both in vitro and in cells. Crucially, these synthetic proteins did not prevent SUMO conjugation either in vitro or in cell-based systems, enabling the specific analysis of SUMO-mediated protein-protein interactions. Furthermore, through structural analysis and molecular modeling, we explored the molecular mechanisms that may underlie their specificity in interfering with either SUMO-1-mediated interactions or interactions mediated by either SUMO-2 or SUMO-3. Not only will these reagents enable investigation of the biological roles of SUMOylation, but the Affimer technology used to generate these synthetic binding proteins could also be exploited to design or validate reagents or therapeutics that target other protein-protein interactions.<br /> (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Subjects :
- Fluorescent Antibody Technique
HEK293 Cells
Humans
Models, Molecular
Molecular Dynamics Simulation
Peptide Fragments pharmacology
SUMO-1 Protein antagonists & inhibitors
Small Ubiquitin-Related Modifier Proteins antagonists & inhibitors
Ubiquitins antagonists & inhibitors
Peptide Library
Protein Interaction Domains and Motifs drug effects
SUMO-1 Protein metabolism
Small Molecule Libraries pharmacology
Small Ubiquitin-Related Modifier Proteins metabolism
Sumoylation drug effects
Ubiquitins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1937-9145
- Volume :
- 10
- Issue :
- 505
- Database :
- MEDLINE
- Journal :
- Science signaling
- Publication Type :
- Academic Journal
- Accession number :
- 29138295
- Full Text :
- https://doi.org/10.1126/scisignal.aaj2005