6bn1
Salvador Hippo SARAH domain complex
Structural highlights
FunctionHIPPO_DROME Plays a key role in 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. The Hippo/SWH signaling pathway inhibits the activity of the transcriptional complex formed by Scalloped (sd) and Yki and the target genes of this pathway include cyclin-E (cycE), diap1 and bantam. Phosphorylates Sav, Wts and Th/DIAP1. Regulates the level of Th/DIAP1 apoptosis inhibitor.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe Hippo pathway controls cell proliferation and differentiation through the precisely tuned activity of a core kinase cassette. The activity of Hippo kinase is modulated by interactions between its C-terminal coiled-coil, termed the SARAH domain, and the SARAH domains of either dRassF or Salvador. Here, we wanted to understand the molecular basis of SARAH domain mediated interactions and their influence on Hippo kinase activity. We focused on Salvador, a positive effector of Hippo activity and the least well characterized SARAH domain-containing protein. We determined the crystal structure of a complex between Salvador and Hippo SARAH domains from Drosophila. This structure provided insight into the organization of the Salvador SARAH domain including a folded N-terminal extension that expands the binding interface with Hippo SARAH domain. We also found this extension improves the solubility of Salvador SARAH domain, enhances binding to Hippo, and is unique to Salvador. We therefore suggest expanding the definition of the Salvador SARAH domain to include this extended region. The heterodimeric assembly observed in the crystal was confirmed by crosslinked mass spectrometry and provided a structural basis for the mutually exclusive interactions of Hippo with either dRassF or Salvador. Of note, Salvador influenced the kinase activity of Mst2, the mammalian Hippo homolog. In co-transfected HEK293T cells, human Salvador increased the levels of Mst2 autophosphorylation and Mst2-mediated phosphorylation of select substrates, whereas Salvador SARAH domain inhibited Mst2 autophosphorylation in vitro. These results suggest Salvador enhances the effects of Hippo kinase activity at multiple points in the Hippo pathway. Salvador has an extended SARAH domain that mediates binding to Hippo kinase.,Cairns L, Tran T, Fowl BH, Patterson A, Kim YJ, Bothner B, Kavran JM J Biol Chem. 2018 Mar 8. pii: RA117.000923. doi: 10.1074/jbc.RA117.000923. PMID:29519817[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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