Comparative analysis of interactions of RASSF1-10.
Members of the RASSF family (RASSF1-10) have been identified as candidate tumour suppressors that are frequently downregulated by promoter hypermethylation in cancers. These proteins carry a common Ras-association (RA) and SARAH domain (RASSF1-6) that can potentially bind Ras oncoproteins and mediate protein-protein interactions with other SARAH domain proteins. However, there is a notable lack of comparative characterisation of the RASSF family, as well as molecular and structural information that facilitate their tumour suppressive functions. As part of our comparative analysis, we modelled the RA and SARAH domains of the RASSF members based on existing structures and predicted their potential interactions. These in silico predictions were compared to in vitro interaction studies with Ras and MST kinase (a SARAH domain-containing protein). Our data shows a diversity of interaction within the RASSF family RA domain, whereas the SARAH domain-mediated interactions for RASSF1-6 are consistent with the predictions. This suggests that different members, despite shared general architecture, could have distinct functional properties. Additionally, we identify a new interacting partner for MST kinase in the form of RASSF7. Current data supports an interaction model where RASSF serves as an adaptor for the assembly of multiple protein complexes and further functional interactions, involving MST kinases and other SARAH domain proteins, which could be regulated by Ras.
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK.
Jia Jia
JJ
Chan
Delphine
D
Flatters
Fernando
F
Rodrigues-Lima
Jun
J
Yan
Konstantinos
K
Thalassinos
Matilda
M
Katan
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism; D000099317:Hippo Kinases
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020559:Monomeric GTP-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C411762:RASSF1 protein, human; C454042:RASSF5 protein, human; C092941:RASSF7 protein, human; C512680:RASSF8 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases