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.
Highlights
There is an acute need for novel drug targets and strategies in the fight against cancer
We performed a detailed sequence comparison of RASSF1-to6 SARAH domains, using multiple sequence alignment obtained with the Clustal Omega software [15,16,17], which allowed us to infer its similarity with structurally resolved homologues (e.g., RASSF5) from the same family
The effect of RASSF1A and RASSF5 over MST1/2 activation is mediated by heterodimerization through the SARAH domain of these proteins
Summary
There is an acute need for novel drug targets and strategies in the fight against cancer. The activation of MST1/2 kinase activity is regulated by either homo-dimerization or by interactions with scaffold proteins such as WW45 and different members of the RASSF family. The regulation of MST1/2 by RASSF scaffolds is a key event in this pathway, but remains poorly understood [3, 5]. The evidence we have so far indicates that the RASSF family members RASSF1A and RASSF5 ( known as NORE1 or RALP) are tumor suppressors that mediate apoptosis through different effectors including MST1/2 kinases, but their exact regulation by RASSF proteins is incompletely understood [6]. RASSF1A and RASSF5 regulate MST1/2 kinase activity by direct protein-protein interaction through their respective SARAH domains [7]. RASSF proteins were shown to be able to activate or inhibit MST1/2 kinase activity upon heterodimerization [5]
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