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bioRxiv · 10.1101/2024.03.07.583872

Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/beta-catenin signaling

Ntourmas, S.·Sachs, M.·Bruckner, M.·Behrens, J.·Bernkopf, D. B.
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Abstract

Activation of the Wnt/{beta}-catenin pathway crucially depends on polymerization of dishevelled 2 (DVL2) into biomolecular condensates. However, given the low affinity of known DVL2 self-interaction sites and its low cellular concentration it is unclear how polymers can form. Here, we detect oligomeric DVL2 complexes at endogenous protein levels, using a biochemical ultracentrifugation assay. We identify a low-complexity region (LCR4) in the C-terminus whose deletion and fusion decreased and increased the complexes, respectively. Notably, LCR4-induced complexes correlated with the formation of microscopically visible multimeric condensates. Adjacent to LCR4, we mapped a conserved domain (CD2) promoting condensates only. Molecularly, LCR4 and CD2 mediated DVL2 self-interaction via aggregating residues and phenylalanine stickers, respectively. Point mutations inactivating these interaction sites impaired Wnt pathway activation by DVL2. Our study discovers DVL2 complexes with functional importance for Wnt/{beta}-catenin signaling. Moreover, we provide evidence that DVL2 condensates form in two steps by pre-oligomerization via high-affinity interaction sites, such as LCR4, and subsequent condensation via low-affinity interaction sites, such as CD2.

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Ntourmas, S., Sachs, M., Bruckner, M., Behrens, J., Bernkopf, D. B.. 2024-03-08. Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/beta-catenin signaling. https://doi.org/10.1101/2024.03.07.583872

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