Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway.
In eukaryotic cells, apoptosis and cell cycle arrest by the Ras --> RASSF --> MST pathway are controlled by the interaction of SARAH (for Salvador/Rassf/Hippo) domains in the C-terminal part of tumor suppressor proteins. The Mst1 SARAH domain interacts with its homologous domain of Rassf1 and Rassf5 (also known as Nore1) by forming a heterodimer that mediates the apoptosis process. Here, we describe the homodimeric structure of the human Mst1 SARAH domain and its heterotypic interaction with the Rassf5 and Salvador (Sav) SARAH domain. The Mst1 SARAH structure forms a homodimer containing two helices per monomer. An antiparallel arrangement of the long alpha-helices (h2/h2') provides an elongated binding interface between the two monomers, and the short 3(10) helices (h1/h1') are folded toward that of the other monomer. Chemical shift perturbation experiments identified an elongated, tight-binding interface with the Rassf5 SARAH domain and a 1:1 heterodimer formation. The linker region between the kinase and the SARAH domain is shown to be disordered in the free protein. These results imply a novel mode of interaction with RASSF family proteins and provide insight into the mechanism of apoptosis control by the SARAH domain.
Hwang
Eunha
E
Magnetic Resonance Team, Korea Basic Science Institute, 804-1 Yangchung-Ri, Ochang, Chungbuk 363-883, Korea.
Ryu
Kyoung-Seok
KS
Pääkkönen
Kimmo
K
Güntert
Peter
P
Cheong
Hae-Kap
HK
Lim
Dae-Sik
DS
Lee
Jie-Oh
JO
Jeon
Young Ho
YH
Cheong
Chaejoon
C
D000595:Amino Acid Sequence; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; C415864:SAV1 protein, human; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases