SARAH Domain-Mediated MST2-RASSF Dimeric Interactions

PLoS Comput Biol. 2016 Oct 7;12(10):e1005051. doi: 10.1371/journal.pcbi.1005051. eCollection 2016 Oct.

Abstract

RASSF enzymes act as key apoptosis activators and tumor suppressors, being downregulated in many human cancers, although their exact regulatory roles remain unknown. A key downstream event in the RASSF pathway is the regulation of MST kinases, which are main effectors of RASSF-induced apoptosis. The regulation of MST1/2 includes both homo- and heterodimerization, mediated by helical SARAH domains, though the underlying molecular interaction mechanism is unclear. Here, we study the interactions between RASSF1A, RASSF5, and MST2 SARAH domains by using both atomistic molecular simulation techniques and experiments. We construct and study models of MST2 homodimers and MST2-RASSF SARAH heterodimers, and we identify the factors that control their high molecular stability. In addition, we also analyze both computationally and experimentally the interactions of MST2 SARAH domains with a series of synthetic peptides particularly designed to bind to it, and hope that our approach can be used to address some of the challenging problems in designing new anti-cancer drugs.

MeSH terms

  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / ultrastructure*
  • Cyclin-Dependent Kinase Inhibitor p15 / chemistry*
  • Cyclin-Dependent Kinase Inhibitor p15 / ultrastructure*
  • Dimerization
  • Drosophila Proteins / chemistry*
  • Drosophila Proteins / ultrastructure*
  • Enzyme Activation
  • Molecular Docking Simulation*
  • Protein Binding
  • Protein Conformation
  • Protein Domains

Substances

  • CDKN2B protein, human
  • Carrier Proteins
  • Cyclin-Dependent Kinase Inhibitor p15
  • Drosophila Proteins
  • RASSF protein, Drosophila

Grants and funding

The authors acknowledge funding from the Science Foundation Ireland (grant no. 06/CE/B1129, for LKN, DM, BNK, WK), the European Union Seventh Framework Program (FP7/2007-2013) ASSET project (grant no. FP7-HEALTH-2010259348, for BNK, WK), the PRIMES project (grant no. FP7-HEALTH-2011278568, for LKN, BNK, WK), and the BBSRC (grant no. BB/N007700/1, for ER). We are also grateful for financial support from the Human Science Frontier Program (GSS, NVB) and from the Irish Research Council (BT, NVB), and wish to thank the DJEI/DES/SFI/HEA Irish Centre for High-End Computing, and the NIH HPC Biowulf cluster at the National Institutes of Health, USA (http://hpc.nih.gov) for the provision of computational support and facilities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.