Regulation of MST complexes and activity via SARAH domain modifications

Abstract

Three elements of the Hippo tumor suppressor pathway - MST1/2, SAV1, and RASSF1-6 - share in common a C-terminal interaction motif termed the SARAH domain. Proteins containing this domain are capable of self-association as homodimers and also of trans-association with other SARAH domain containing proteins as well as selected additional proteins that lack this domain. Recently, the association of MST1/2 with itself or with other proteins has been shown to be regulated by phosphorylation at sites near or within the SARAH domain. In this review, we focus on recent findings regarding the regulation of such MST1/2 interactions, with an emphasis on the effects of these events on Hippo pathway activity.

Keywords: SARAH domain; cancer; dimerization; hippo pathway; protein kinases; signal transduction.

Fig. 1.. Complexes between SARAH-domain containing proteins.

(A) Examples of homotypic protein complexes involving MST1 and RASSF1, respectively. (B) Examples of heterodimeric interactions involving the SARAH domain of RASSF1A and MST2, respectively, with the kinase domains of Aurora A and RAF1, respectively.

Fig. 2.. Cartoon and stick representation of the crystal structure of Human SARAH domain.

(A) Ribbons diagram of the MST1 SARAH domain (green) (PDB ID 2JO8), showing the amino acids Y433, S438 and T440 residues (colored). (B) Ribbons representation of the MST2 SARAH domain (green) (PDB ID 4OH9), showing the amino acid S444 residue (colored). The super-secondary structures were prepared using the PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC. Note that the SARAH domain is showed as a monomer for clarity, but is derived from the dimeric form. (C) Multiple sequence alignment of SARAH domain of MST1, MST2, RASSF1, RSAAF5 and SAV1 proteins. The UniProt (62) accession numbers are shown after the names of the sequences. The conserved residues are indicated by the default blue colouring scheme of the Jalview program. The residues shown in A and B are highlighted with red background. The structural alignment was created in T-Coffee (63) and the picture using Jalview 2 (64).