orals 5th Asia-Pacific NMR Symposium 2013

Dimeric interaction of the SARAH domains in Mst1, Mst2 and Rassf5 (#86)

Eunha Hwang 1 , Hae-Kap Cheong 1 , Chaejoon Cheong 1 , Young Ho Jeon 2
  1. Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Korea
  2. Korea University, Sejong City, South Korea

In eukaryotic cells, apoptosis and cell cycle arrest by the Hippo signaling 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 and heterodimeric structure of the human Mst1, Mst2 and Rassf5 SARAH domains and their interactions. 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.