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

Hwang, Eunha; Cheong, Hae‐Kap; Mushtaq, Ameeq Ul; Kim, Hye Yeon; Yeo, Kwon Joo; Kim, Eun‐Hee; Lee, Woo Cheol; Hwang, Kwang Yeon; Cheong, Chaejoon; Jeon, Young Ho

doi:10.1107/s139900471400947x

Cited by 42 publications

(54 citation statements)

References 42 publications

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“…Third, a sharp distortion of the α-helix of Mst1 monomer was observed in the Mst1-RASSF5 heterodimer at P453 and P472. Interestingly, this study also showed that Rassf5-Mst1 heterodimers are more stable than the Mst1 homodimer, as there are more extensive polar and nonpolar interactions in the heterodimer [40]. As discussed in the next section, the higher affinity for heterodimer formation may have implications regarding Mst activation, and also raise questions about the abundance of endogenous Mst/Mst homodimers vs. heterodimeric complexes with other SARAH-domain containing proteins.…”

Section: Mst1/2: Domain Structure and Dimerizationmentioning

confidence: 98%

Regulation of mammalian Ste20 (Mst) kinases

Rawat

Chernoff

2015

Trends in Biochemical Sciences

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Summary Initially identified as mammalian homologs to yeast Ste20 kinases, the Mst1/2 kinases have been widely investigated subsequent to their rediscovery as key components of the Hippo tumor suppressor pathway in flies. To date, our understanding of Mst substrates and downstream signaling outstrips our knowledge of how these enzymes are controlled by upstream signals. While much remains to be discovered regarding the mechanisms of Mst regulation, it is clear that Mst1 kinase activity is governed at least in part by its state of dimerization, including self-association and also heterodimerization with a variety of other signaling partners. Here, we review the basic architecture of Mst signaling and function and discuss recent advances in our understanding of how these important kinases are regulated.

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Section: Mst1/2: Domain Structure and Dimerizationmentioning

confidence: 98%

Regulation of mammalian Ste20 (Mst) kinases

Rawat

Chernoff

2015

Trends in Biochemical Sciences

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“…1,2 RASSF5 activates mammalian sterile 20-like kinase 1/2 (MST1/2) in the Hippo pathway. 3–9 Hippo’s signaling stimulates phosphorylation and thereby activation of a core kinase cascade including MST1/2 and large tumor suppressor 1/2 (LATS1/2), leading to phosphorylation of Yes associated protein 1 (YAP1). 10,11 YAP1’s phosphorylation encodes its degradation, thus abolishing its transcriptional activity.…”

Section: Introductionmentioning

confidence: 99%

The dynamic mechanism of RASSF5 and MST kinase activation by Ras

Liao

Jang

Tsai

et al. 2017

Phys. Chem. Chem. Phys.

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As a tumor suppressor, RASSF5 (NORE1A) activates MST1/2 thereby modulating the Hippo pathway. Structurally, activation involves RASSF5 and MST1/2 swapping their SARAH domains to form a SARAH heterodimer. This exposes the MST1/2 kinase domain which homodimerizes, leading to trans-autophosphorylation. The SARAH-SARAH interaction shifts RASSF5 away from its autoinhibited state and relieves MST1/2 autoinhibition. Separate crystal structures are available for the RA (Ras association) domain and SARAH dimer, where SARAH is a long straight α-helix. Using all-atom molecular dynamics simulations, we modeled the RASSF5 RA with a covalently connected SARAH to elucidate the dynamic mechanism of how SARAH mediates between autoinhibition and Ras triggered-activation. Our results show that in inactive RASSF5 the RA domain retains SARAH, yielding a self-associated conformation in which SARAH is in a kinked α-helical motif that increases the binding interface. When RASSF5 binds K-Ras4B-GTP, the equilibrium shifts toward SARAH’s interacting with MST. Since the RA/SARAH affinity is relatively low, whereas that of the SARAH heterodimer is in the nM range, we suggest that RASSF5 exerts its tumor suppressor action through competition with other Ras effectors for Ras effector binding site, as well as coincidentally its recruitment to the membrane to help MST activation. Thus, SARAH plays a key role in RASSF5’s tumor suppression action by linking the two major pathways in tumor cell proliferation: Ras and the MAPK (tumor cell proliferation-promoting) pathway, and the Hippo (tumor cell proliferation-suppressing) pathway.

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“…The SARAH domain of MST1/2 forms heterodimer with that of RASSF5 in a manner similar to their homodimerization ( Fig. 1B) (PDB codes: 4LGD and 4OH8) [44,53,57]. The interface of MST1/2-RASSF5 heterodimer also resembles those of their homodimers, but the heterodimers have more intermolecular hydrogen bonds and more extensive hydrophobic interactions than the homodimers, which makes them more stable than the homodimers, as supported by results from urea-induced denaturation experiment [53].…”

Section: Core Kinase Cascadementioning

confidence: 78%

“…The structures of MST1/2 and RASSF5 SARAH homodimers or heterodimers have been determined (Fig. 1B) [44,48,[52][53][54]. The SARAH domain of MST1/2 or RASSF5 alone forms a symmetric homodimer (PDB codes: 2JO8, 2YMY, 4HKD, 4L0N, 4NR2, and 4OH9).…”

Section: Core Kinase Cascadementioning

confidence: 99%

Structural dissection of Hippo signaling

Shi¹,

Shi

Zhou

2015

ABBS

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The Hippo pathway controls cell number and organ size by restricting cell proliferation and promoting apoptosis, and thus is a key regulator in development and homeostasis. Dysfunction of the Hippo pathway correlates with many pathological conditions, especially cancer. Hippo signaling also plays important roles in tissue regeneration and stem cell biology. Therefore, the Hippo pathway is recognized as a crucial target for cancer therapy and regeneration medicine. To date, structures of several key components in Hippo signaling have been determined. In this review, we summarize current available structural studies of the Hippo pathway, which may help to improve our understanding of its regulatory mechanisms, as well as to facilitate further functional studies and potential therapeutic interventions.

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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.

Cited by 42 publications

References 42 publications

Regulation of mammalian Ste20 (Mst) kinases

Regulation of mammalian Ste20 (Mst) kinases

The dynamic mechanism of RASSF5 and MST kinase activation by Ras

Structural dissection of Hippo signaling

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