7edr

From Proteopedia

The crystal structure of the FERM and C-terminal domain complex of Drosophila Merlin

Structural highlights

7edr is a 4 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.527Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MERH_DROME Regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein Hippo (Hpo), in complex with its regulatory protein Salvador (Sav), phosphorylates and activates Warts (Wts) in complex with its regulatory protein Mats, which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein. Mer acts synergistically along with Ex and Kibra to regulate the Hippo signaling pathway.^[1] ^[2]

Publication Abstract from PubMed

NF2/Merlin is an upstream regulator of hippo pathway, and it has two states: an auto-inhibited "closed" state and an active "open" form. Previous studies showed that Drosophila Merlin adopts a more closed conformation. However, the molecular mechanism of conformational regulation remains poorly understood. Here, we first confirmed the strong interaction between FERM and the C-terminal domain (CTD) of Merlin, and then determined the crystal structure of the FERM/CTD complex, which reveals the structural basis of Merlin adopting a more closed conformation compared to its human cognate NF2. Interestingly, we found that the conserved lipid-binding site of Merlin might be masked by a linker. Confocal analyses confirmed that all putative lipid-binding site are very important for the membranal location of Merlin. More, we found that the phosphomimic Thr616Asp mutation weakens the interaction between FERM and CTD of Merlin. Collectively, the crystal structure of the FERM/CTD complex not only provides a mechanistic explanation of functionally dormant conformation of Merlin may also serve as a foundation for revealing the mechanism of conformational regulation of Merlin.

The crystal structure of the FERM and C-terminal domain complex of Drosophila Merlin.,Zhang F, Liu B, Gao Y, Long J, Zhou H Biochem Biophys Res Commun. 2021 May 14;553:92-98. doi: , 10.1016/j.bbrc.2021.03.065. Epub 2021 Mar 22. PMID:33765559^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell. 2010 Feb 16;18(2):288-99. doi: 10.1016/j.devcel.2009.12.012. PMID:20159598 doi:http://dx.doi.org/10.1016/j.devcel.2009.12.012
↑ McCartney BM, Fehon RG. Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin. J Cell Biol. 1996 May;133(4):843-52. PMID:8666669 doi:10.1083/jcb.133.4.843
↑ Zhang F, Liu B, Gao Y, Long J, Zhou H. The crystal structure of the FERM and C-terminal domain complex of Drosophila Merlin. Biochem Biophys Res Commun. 2021 May 14;553:92-98. PMID:33765559 doi:10.1016/j.bbrc.2021.03.065