MST2-RASSF protein–protein interactions through SARAH domains

Abstract

The detailed, atomistic-level understanding of molecular signaling along the tumor-suppressive Hippo signaling pathway that controls tissue homeostasis by balancing cell proliferation and death through apoptosis is a promising avenue for the discovery of novel anticancer drug targets. The activation of kinases such as Mammalian STE20-Like Protein Kinases 1 and 2 (MST1 and MST2)-modulated through both homo- and heterodimerization (e.g. interactions with Ras association domain family, RASSF, enzymes)-is a key upstream event in this pathway and remains poorly understood. On the other hand, RASSFs (such as RASSF1A or RASSF5) act as important apoptosis activators and tumor suppressors, although their exact regulatory roles are also unclear. We present recent molecular studies of signaling along the Ras-RASSF-MST pathway, which controls growth and apoptosis in eukaryotic cells, including a variety of modern molecular modeling and simulation techniques. Using recently available structural information, we discuss the complex regulatory scenario according to which RASSFs perform dual signaling functions, either preventing or promoting MST2 activation, and thus control cell apoptosis. Here, we focus on recent studies highlighting the special role being played by the specific interactions between the helical Salvador/RASSF/Hippo (SARAH) domains of MST2 and RASSF1a or RASSF5 enzymes. These studies are crucial for integrating atomistic-level mechanistic information about the structures and conformational dynamics of interacting proteins, with information available on their system-level functions in cellular signaling.

RASSF1A is required for the maintenance of nuclear actin levels

“…RASSF1A directly binds Mammalian STE20-Like Protein Kinases 1 and 2 (MST1 and MST2) to support maintenance of MST1/2 phosphorylation and activation (Sánchez-Sanz et al, 2016). Interestingly, mass spectrometry analysis of MST2 eluted fractions from HeLa lysates identified confidently the interaction between MST2 Lamin A/C (Figs 2A, EV2A) and suggested a potential interaction with Lamin B1.…”

Biophysical characterization of SARAH domain–mediated multimerization of Hippo pathway complexes in Drosophila

“…SARAH domains were first identified as a conserved coiled-coil region located at the Ctermini of three members of the Hippo pathway, Salvador, dRassF, and Hippo, and were named after each (23). Dimeric, trimeric, and tetrameric assemblies of coiled-coils have been proposed, but the preponderance of evidence supports a dimeric assembly with limited evidence for tetrameric assemblies and no evidence for trimeric ones (14,18,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Structural studies have each revealed a conserved arrangement of two anti-parallel coiled-coils with each monomer adopting a short 3/10-helix followed by a turn and a long a-helix (18,(25)(26)(27)(28)(29)(30)(31)(32).…”

RASSF 1A is required for the maintenance of nuclear actin levels

“…RASSF1A directly binds mammalian STE20-like protein kinases 1 and 2 (MST1 and MST2) to support maintenance of MST1/2 phosphorylation and activation (Sánchez-Sanz et al, 2016). Interestingly, mass spectrometry analysis of MST2 eluted fractions from HeLa lysates identified confidently the interaction between MST2 and Lamin A/C (Figs 2A and EV2A) and suggested a potential interaction with Lamin B1.…”