Salvador has an extended SARAH domain that mediates binding to Hippo kinase

被引:14
作者
Cairns, Leah [1 ]
Thao Tran [1 ]
Fowl, Brendan H. [1 ]
Patterson, Angela [2 ]
Kim, Yoo Jin [1 ]
Bothner, Brian [2 ]
Kavran, Jennifer M. [1 ,3 ,4 ]
机构
[1] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 20215 USA
[2] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA
[3] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 20215 USA
[4] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 20215 USA
基金
美国国家卫生研究院;
关键词
NDR-PROTEIN-KINASE; CELL-CYCLE EXIT; TUMOR-SUPPRESSOR; HELIX GEOMETRY; WW DOMAIN; PROLIFERATION ARREST; PROMOTES APOPTOSIS; STRUCTURAL BASIS; MST1; KINASE; DROSOPHILA;
D O I
10.1074/jbc.RA117.000923
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The 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 that this extension improves the solubility of the 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 cross-linked MS 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.
引用
收藏
页码:5532 / 5543
页数:12
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