Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 22, Pages 9236-9241Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0610716104
Keywords
tumor suppressor; cell cycle arrest; Hippo; Salvador
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Funding
- Ministry of Education, Science & Technology (MoST), Republic of Korea [kaist40] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2006-07635] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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