title: Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway.
abstract: Despite recent progress in research on the Hippo signalling pathway, the structural information available in this area is extremely limited. Intriguingly, the homodimeric and heterodimeric interactions of mammalian sterile 20-like (MST) kinases through the so-called `SARAH' (SAV/RASSF/HPO) domains play a critical role in cellular homeostasis, dictating the fate of the cell regarding cell proliferation or apoptosis. To understand the mechanism of the heterodimerization of SARAH domains, the three-dimensional structures of an MST1-RASSF5 SARAH heterodimer and an MST2 SARAH homodimer were determined by X-ray crystallography and were analysed together with that previously determined for the MST1 SARAH homodimer. While the structure of the MST2 homodimer resembled that of the MST1 homodimer, the MST1-RASSF5 heterodimer showed distinct structural features. Firstly, the six N-terminal residues (Asp432-Lys437), which correspond to the short N-terminal 3₁₀-helix h1 kinked from the h2 helix in the MST1 homodimer, were disordered. Furthermore, the MST1 SARAH domain in the MST1-RASSF5 complex showed a longer helical structure (Ser438-Lys480) than that in the MST1 homodimer (Val441-Lys480). Moreover, extensive polar and nonpolar contacts in the MST1-RASSF5 SARAH domain were identified which strengthen the interactions in the heterodimer in comparison to the interactions in the homodimer. Denaturation experiments performed using urea also indicated that the MST-RASSF heterodimers are substantially more stable than the MST homodimers. These findings provide structural insights into the role of the MST1-RASSF5 SARAH domain in apoptosis signalling.
authors.affiliation: Division of Magnetic Resonance Research, Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883, Republic of Korea.
authors.forename: Eunha
authors.initials: E
authors.lastname: Hwang
authors.affiliation: Division of Magnetic Resonance Research, Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883, Republic of Korea.
authors.forename: Hae-Kap
authors.initials: HK
authors.lastname: Cheong
authors.affiliation: College of Pharmacy, Korea University, Sejong-ro, Sejong 339-700, Republic of Korea.
authors.forename: Ameeq
authors.initials: A
authors.lastname: Ul Mushtaq
authors.affiliation: Division of Magnetic Resonance Research, Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883, Republic of Korea.
authors.forename: Hye-Yeon
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Division of Magnetic Resonance Research, Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883, Republic of Korea.
authors.forename: Kwon Joo
authors.initials: KJ
authors.lastname: Yeo
authors.affiliation: Division of Magnetic Resonance Research, Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883, Republic of Korea.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Woo Cheol
authors.initials: WC
authors.lastname: Lee
authors.affiliation: Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Kwang Yeon
authors.initials: KY
authors.lastname: Hwang
authors.affiliation: Division of Magnetic Resonance Research, Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883, Republic of Korea.
authors.forename: Chaejoon
authors.initials: C
authors.lastname: Cheong
authors.affiliation: College of Pharmacy, Korea University, Sejong-ro, Sejong 339-700, Republic of Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D019281:Dimerization; D000090683:Hippo Signaling Pathway; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D017346:Protein Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases; C093290:MAP3K10 protein, human
keywords: Hippo signalling pathway; MST; RASSF; SARAH domains