7BQF

Dimerization of SAV1 WW tandem

Summary for 7BQF

• Entry DOI: 10.2210/pdb7bqf/pdb
• Descriptor: Protein salvador homolog 1, 1,4-DIETHYLENE DIOXIDE (3 entities in total)
• Functional Keywords: hippo pathway, ww domain, sav1, signaling protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 10835.87

Authors

Lin, Z.,Zhang, M. (deposition date: 2020-03-24, release date: 2020-09-23, Last modification date: 2024-10-09)

Primary citation

Lin, Z.,Xie, R.,Guan, K.,Zhang, M.
A WW Tandem-Mediated Dimerization Mode of SAV1 Essential for Hippo Signaling.
Cell Rep, 32:108118-108118, 2020

PubMed 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.

PubMed: 32905778
DOI: 10.1016/j.celrep.2020.108118

Experimental method

X-RAY DIFFRACTION (1.70037617383 Å)