MST1 and Nore1 interactions in apoptotic signalling

The molecular switch Ras exhibits its biological function like control of growth, differentiation and apoptosis through the interaction with various effectors. Growth-inhibitory properties of Ras are mediated via Rassf proteins (Ras association domain family). Thus, tumor suppressor Rassf5 (Nore1) binds directly to Ras-GTP via the Ras Binding Domain (RBD). It also forms homodimers as well as heterodimers with other Rassf proteins and with the proapoptotic serine/threonine Mammalian Sterile 20-like kinase (MST1) - mediated by their common conserved coiled-coil like C-terminal Sav/Rassf/Hpo (SARAH) domains [1,2]. This unique interaction motif connects the proteins involved in Ras-mediated apoptosis [3-6]. We have investigated the structure, thermodynamics and kinetics of association/dissociation/unfolding mechanism of SARAH domain. The dissociation of the dimers triggers also conformational changes in the secondary structure, mainly from alpha helix to random coil. The homodimers and the heterodimer exist in a thermodynamic equilibrium. The low lifetime of Nore1 is characteristic for an adaptor protein, also supported by the tight interaction between Nore1 RBD and Ras-GTP, shown previously [7]. In conclusion, an in depth thermodynamic and kinetic study of the interchange between MST1 and Nore1 dimers is reported. The involvement in other potential pathways linked to growth control is also addressed.