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Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway.

Li Y, Zhou H, Li F, Chan SW, Lin Z, Wei Z, Yang Z, Guo F, Lim CJ, Xing W, Shen Y, Hong W, Long J, Zhang M - Cell Res. (2015)

Bottom Line: Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation.Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation.Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong, China.

ABSTRACT
The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4(DCAF1). Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.

No MeSH data available.


Related in: MedlinePlus

The overall structure of the Merlin-FERM/Merlin-CTD complex. (A) Ribbon diagram showing the crystal structure of the stabilized, fully closed Merlin-FERM/Merlin-CTD complex. S518D is shown in the stick model and colored in red. (B) Comparison of the structures of the Merlin FERM/CTD complex and the Moesin FERM/CTD complex (PDB code: 1EF1). In this representation, the Merlin-CTD and Moesin-CTD are shown as ribbons, and the Merlin-FERM is drawn in the surface model based on the degree of their amino acid sequence conservation between Merlin and ERMs. The N-terminal half of Merlin α1CTD is boxed in red to emphasize its structural uniqueness. (C) Sequence alignment of the CTD regions from Merlin across different species and human Moesin-CTD. Secondary structural elements for Merlin-CTD and Moesin-CTD are indicated above and below the alignment, respectively. Residues involved in the auto-inhibition of Merlin are emphasized in orange and S518 is highlighted in red and with an asterisk. The residues within the red box form the first half of α1CTD highlighted in red box in B. (D) Molecular details of the Merlin FERM/CTD interaction. (E, F) Ribbon-dot model (E) and a schematic diagram (F) summarizing 21 human cancer-related missense mutations. The mutations that are predicted to interfere with the folding of FERM are shown in red; the mutations that may alter the auto-inhibition and/or AMOT binding of Merlin are colored in cyan and blue.
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fig2: The overall structure of the Merlin-FERM/Merlin-CTD complex. (A) Ribbon diagram showing the crystal structure of the stabilized, fully closed Merlin-FERM/Merlin-CTD complex. S518D is shown in the stick model and colored in red. (B) Comparison of the structures of the Merlin FERM/CTD complex and the Moesin FERM/CTD complex (PDB code: 1EF1). In this representation, the Merlin-CTD and Moesin-CTD are shown as ribbons, and the Merlin-FERM is drawn in the surface model based on the degree of their amino acid sequence conservation between Merlin and ERMs. The N-terminal half of Merlin α1CTD is boxed in red to emphasize its structural uniqueness. (C) Sequence alignment of the CTD regions from Merlin across different species and human Moesin-CTD. Secondary structural elements for Merlin-CTD and Moesin-CTD are indicated above and below the alignment, respectively. Residues involved in the auto-inhibition of Merlin are emphasized in orange and S518 is highlighted in red and with an asterisk. The residues within the red box form the first half of α1CTD highlighted in red box in B. (D) Molecular details of the Merlin FERM/CTD interaction. (E, F) Ribbon-dot model (E) and a schematic diagram (F) summarizing 21 human cancer-related missense mutations. The mutations that are predicted to interfere with the folding of FERM are shown in red; the mutations that may alter the auto-inhibition and/or AMOT binding of Merlin are colored in cyan and blue.

Mentions: Identification of a fully closed conformation of Merlin (A585W-Merlin) provided us with a unique opportunity to obtain the crystal structure of the head-to-tail auto-inhibited form of Merlin, which is otherwise not feasible due to the conformational dynamics of WT-Merlin. We were able to obtain high-diffraction quality crystals of Merlin-FERM in complex with Merlin-CTD bearing S518D/A585W substitutions and solved the complex structure (Figure 2A and Supplementary information, Table S1).


Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway.

Li Y, Zhou H, Li F, Chan SW, Lin Z, Wei Z, Yang Z, Guo F, Lim CJ, Xing W, Shen Y, Hong W, Long J, Zhang M - Cell Res. (2015)

The overall structure of the Merlin-FERM/Merlin-CTD complex. (A) Ribbon diagram showing the crystal structure of the stabilized, fully closed Merlin-FERM/Merlin-CTD complex. S518D is shown in the stick model and colored in red. (B) Comparison of the structures of the Merlin FERM/CTD complex and the Moesin FERM/CTD complex (PDB code: 1EF1). In this representation, the Merlin-CTD and Moesin-CTD are shown as ribbons, and the Merlin-FERM is drawn in the surface model based on the degree of their amino acid sequence conservation between Merlin and ERMs. The N-terminal half of Merlin α1CTD is boxed in red to emphasize its structural uniqueness. (C) Sequence alignment of the CTD regions from Merlin across different species and human Moesin-CTD. Secondary structural elements for Merlin-CTD and Moesin-CTD are indicated above and below the alignment, respectively. Residues involved in the auto-inhibition of Merlin are emphasized in orange and S518 is highlighted in red and with an asterisk. The residues within the red box form the first half of α1CTD highlighted in red box in B. (D) Molecular details of the Merlin FERM/CTD interaction. (E, F) Ribbon-dot model (E) and a schematic diagram (F) summarizing 21 human cancer-related missense mutations. The mutations that are predicted to interfere with the folding of FERM are shown in red; the mutations that may alter the auto-inhibition and/or AMOT binding of Merlin are colored in cyan and blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493278&req=5

fig2: The overall structure of the Merlin-FERM/Merlin-CTD complex. (A) Ribbon diagram showing the crystal structure of the stabilized, fully closed Merlin-FERM/Merlin-CTD complex. S518D is shown in the stick model and colored in red. (B) Comparison of the structures of the Merlin FERM/CTD complex and the Moesin FERM/CTD complex (PDB code: 1EF1). In this representation, the Merlin-CTD and Moesin-CTD are shown as ribbons, and the Merlin-FERM is drawn in the surface model based on the degree of their amino acid sequence conservation between Merlin and ERMs. The N-terminal half of Merlin α1CTD is boxed in red to emphasize its structural uniqueness. (C) Sequence alignment of the CTD regions from Merlin across different species and human Moesin-CTD. Secondary structural elements for Merlin-CTD and Moesin-CTD are indicated above and below the alignment, respectively. Residues involved in the auto-inhibition of Merlin are emphasized in orange and S518 is highlighted in red and with an asterisk. The residues within the red box form the first half of α1CTD highlighted in red box in B. (D) Molecular details of the Merlin FERM/CTD interaction. (E, F) Ribbon-dot model (E) and a schematic diagram (F) summarizing 21 human cancer-related missense mutations. The mutations that are predicted to interfere with the folding of FERM are shown in red; the mutations that may alter the auto-inhibition and/or AMOT binding of Merlin are colored in cyan and blue.
Mentions: Identification of a fully closed conformation of Merlin (A585W-Merlin) provided us with a unique opportunity to obtain the crystal structure of the head-to-tail auto-inhibited form of Merlin, which is otherwise not feasible due to the conformational dynamics of WT-Merlin. We were able to obtain high-diffraction quality crystals of Merlin-FERM in complex with Merlin-CTD bearing S518D/A585W substitutions and solved the complex structure (Figure 2A and Supplementary information, Table S1).

Bottom Line: Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation.Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation.Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong, China.

ABSTRACT
The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4(DCAF1). Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.

No MeSH data available.


Related in: MedlinePlus