A WW Tandem-Mediated Dimerization Mode of SAV1 Essential for Hippo Signaling

Zhijie Lin; Ruiling Xie; Kunliang Guan; Mingjie Zhang

doi:10.1016/j.celrep.2020.108118

A WW Tandem-Mediated Dimerization Mode of SAV1 Essential for Hippo Signaling

Cell Rep. 2020 Sep 8;32(10):108118. doi: 10.1016/j.celrep.2020.108118.

Authors

Zhijie Lin¹, Ruiling Xie², Kunliang Guan³, Mingjie Zhang⁴

Affiliations

¹ Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
² Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Otolaryngology, Head & Neck Surgery, Peking University First Hospital, Beijing 100034, China.
³ Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Electronic address: mzhang@ust.hk.

Abstract

The canonical mammalian Hippo pathway contains a core kinase signaling cascade requiring upstream MST to form a stable complex with SAV1 in order to phosphorylate the downstream LATS/MOB complex. Though SAV1 dimerization is essential for the trans-activation of MST, the molecular mechanism underlying SAV1 dimerization is unclear. Here, we discover that the SAV1 WW tandem containing a short Pro-rich extension immediately following the WW tandem (termed as "WW12ex") forms a highly stable homodimer. The crystal structure of SAV1 WW12ex reveals that the Pro-rich extension of one subunit binds to both WW domains from the other subunit. Thus, SAV1 WW12ex forms a domain-swapped dimer instead of a WW2 homodimerization-mediated dimer. The WW12ex-mediated dimerization of SAV1 is required for the MST/SAV1 complex assembly and MST kinase activation. Finally, we show that several cancer-related SAV1 variants disrupt SAV1 dimer formation, and thus, these mutations may impair the tumor-suppression activity of SAV1.

Keywords: Hippo pathway; MST1; MST2; SAV1; WW domain; domain swapping; supramodule; tandem domains.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Cycle Proteins / metabolism*
Dimerization
Hippo Signaling Pathway
Humans
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction

Substances

Cell Cycle Proteins
SAV1 protein, human
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding