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Title: Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway

Abstract

The heterodimeric structure of the MST1 and RASSF5 SARAH domains is presented. A comparison of homodimeric and heterodimeric interactions provides a structural basis for the preferential association of the SARAH heterodimer. 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 3{sub 10}-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 andmore » 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.« less

Authors:
 [1];  [1];  [2]; ; ;  [1]; ;  [3];  [1]
  1. Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883 (Korea, Republic of)
  2. Korea University, Sejong-ro, Sejong 339-700 (Korea, Republic of)
  3. Korea University, Seoul 136-701 (Korea, Republic of)
Publication Date:
OSTI Identifier:
22347771
Resource Type:
Journal Article
Journal Name:
Acta Crystallographica. Section D: Biological Crystallography
Additional Journal Information:
Journal Volume: 70; Journal Issue: Pt 7; Other Information: PMCID: PMC4089488; PMID: 25004971; PUBLISHER-ID: wa5070; OAI: oai:pubmedcentral.nih.gov:4089488; Copyright (c) Hwang et al. 2014; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0907-4449
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; CELL PROLIFERATION; CRYSTALLOGRAPHY; CRYSTALS; INTERACTIONS; UREA

Citation Formats

Hwang, Eunha, Korea University, Seoul 136-701, Cheong, Hae-Kap, Mushtaq, Ameeq Ul, Kim, Hye-Yeon, Yeo, Kwon Joo, Kim, Eunhee, Lee, Woo Cheol, Hwang, Kwang Yeon, Cheong, Chaejoon, Jeon, Young Ho, E-mail: cheong@kbsi.re.kr, and Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883. Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway. Denmark: N. p., 2014. Web. doi:10.1107/S139900471400947X.
Hwang, Eunha, Korea University, Seoul 136-701, Cheong, Hae-Kap, Mushtaq, Ameeq Ul, Kim, Hye-Yeon, Yeo, Kwon Joo, Kim, Eunhee, Lee, Woo Cheol, Hwang, Kwang Yeon, Cheong, Chaejoon, Jeon, Young Ho, E-mail: cheong@kbsi.re.kr, & Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883. Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway. Denmark. https://doi.org/10.1107/S139900471400947X
Hwang, Eunha, Korea University, Seoul 136-701, Cheong, Hae-Kap, Mushtaq, Ameeq Ul, Kim, Hye-Yeon, Yeo, Kwon Joo, Kim, Eunhee, Lee, Woo Cheol, Hwang, Kwang Yeon, Cheong, Chaejoon, Jeon, Young Ho, E-mail: cheong@kbsi.re.kr, and Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883. 2014. "Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway". Denmark. https://doi.org/10.1107/S139900471400947X.
@article{osti_22347771,
title = {Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway},
author = {Hwang, Eunha and Korea University, Seoul 136-701 and Cheong, Hae-Kap and Mushtaq, Ameeq Ul and Kim, Hye-Yeon and Yeo, Kwon Joo and Kim, Eunhee and Lee, Woo Cheol and Hwang, Kwang Yeon and Cheong, Chaejoon and Jeon, Young Ho, E-mail: cheong@kbsi.re.kr and Korea Basic Science Institute, Ochang-eup Yeongudangiro 162, Cheongwon-gun, Chungbuk 363-883},
abstractNote = {The heterodimeric structure of the MST1 and RASSF5 SARAH domains is presented. A comparison of homodimeric and heterodimeric interactions provides a structural basis for the preferential association of the SARAH heterodimer. 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 3{sub 10}-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.},
doi = {10.1107/S139900471400947X},
url = {https://www.osti.gov/biblio/22347771}, journal = {Acta Crystallographica. Section D: Biological Crystallography},
issn = {0907-4449},
number = Pt 7,
volume = 70,
place = {Denmark},
year = {Tue Jul 01 00:00:00 EDT 2014},
month = {Tue Jul 01 00:00:00 EDT 2014}
}