SARAH Domain-mediated MST2-RASSF Dimeric Interactions

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Title: SARAH Domain-mediated MST2-RASSF Dimeric Interactions
Authors: Sánchez-Sanz, Goar
Tywoniuk, Bartłomiej
Matallanas, David
Romano, David
Nguyen, Lan K.
Kholodenko, Boris N.
Rosta, Edina
Kolch, Walter
Buchete, Nicolae-Viorel
Permanent link: http://hdl.handle.net/10197/9462
Date: 7-Oct-2016
Abstract: We model the conformational changes and protein-protein interactions of enzymes involved in signaling along the Hippo pathway¿a key molecular mechanism that controls the process of programmed cell death in eukaryotic cells, including cells affected by cancer. Combining modern computational modeling techniques with experimental information from X-ray crystallography and systems biology studies, can unveil detailed molecular interactions and lead to novel drugs. Here, we study the atomistic mechanisms and interactions between MST2 and RASSF-type kinases, through their respective SARAH domains¿highly conserved, long, terminal α-helices, which play essential roles in the activation of MST kinases and, therefore, in modulating apoptosis. In spite of their key roles in mediating cell signaling pathways, there is little structural information available for the RASSF SARAH domains and their dimerization with the MST2 SARAH domains. In particular, the RASSF1A crystal structure is not available yet. Here, we model, refine and validate atomistic structural models of dimers of the RASSF1A and MST2 SARAH domains, studying the interaction and the dynamic behavior of these molecular complexes using homology modeling, docking and full atomistic molecular dynamics simulations. Experimentally, we validate our approach by designing a novel peptide that can disrupt effectively MST2 homo and hetero SARAH dimers.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Irish Research Council
Science Foundation Ireland
Type of material: Journal Article
Publisher: Public Library of Science
Journal: PLoS Computational Biology
Volume: 12
Issue: 10
Copyright (published version): 2016 the Authors
Keywords: Competing protein interactionsSARAH domainsSignaling switchesApoptosisCell fate decisionMolecular dynamics
DOI: 10.1371/journal.pcbi.1005051
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
Physics Research Collection
SBI Research Collection
Medicine Research Collection

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