Journal
CELL REPORTS
Volume 32, Issue 10, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108118
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Funding
- RGC of Hong Kong [AoE-M09-12, C6004-17G]
- Asia Foundation for Cancer Research [AFCR17SC01]
- National Institutes of Health [CA196878, CA217642, GM51586, DEO15964]
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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.
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