Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/β-catenin signaling
Activation of the Wnt/β-catenin pathway crucially depends on the 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 oligome...
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eLife Sciences Publications Ltd
2024-12-01
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| Online Access: | https://elifesciences.org/articles/96841 |
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| author | Senem Ntourmas Martin Sachs Petra Paclíková Martina Brückner Vítězslav Bryja Jürgen Behrens Dominic B Bernkopf |
| author_facet | Senem Ntourmas Martin Sachs Petra Paclíková Martina Brückner Vítězslav Bryja Jürgen Behrens Dominic B Bernkopf |
| author_sort | Senem Ntourmas |
| collection | DOAJ |
| description | Activation of the Wnt/β-catenin pathway crucially depends on the 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 in human cell lines, 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/β-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. |
| format | Article |
| id | doaj-art-d5b61e976be743fca0a2384c105e1095 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-d5b61e976be743fca0a2384c105e10952024-12-09T16:50:43ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.96841Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/β-catenin signalingSenem Ntourmas0Martin Sachs1Petra Paclíková2Martina Brückner3Vítězslav Bryja4https://orcid.org/0000-0002-9136-5085Jürgen Behrens5Dominic B Bernkopf6https://orcid.org/0000-0003-4870-5248Experimental Medicine II, Nikolaus-Fiebiger-Center, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, GermanyExperimental Medicine II, Nikolaus-Fiebiger-Center, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, GermanyDepartment of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech RepublicExperimental Medicine II, Nikolaus-Fiebiger-Center, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, GermanyDepartment of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech RepublicExperimental Medicine II, Nikolaus-Fiebiger-Center, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, GermanyExperimental Medicine II, Nikolaus-Fiebiger-Center, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, GermanyActivation of the Wnt/β-catenin pathway crucially depends on the 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 in human cell lines, 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/β-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.https://elifesciences.org/articles/96841dishevelledDVL2Wnt signalingbiomolecular condensatesparalogs |
| spellingShingle | Senem Ntourmas Martin Sachs Petra Paclíková Martina Brückner Vítězslav Bryja Jürgen Behrens Dominic B Bernkopf Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/β-catenin signaling eLife dishevelled DVL2 Wnt signaling biomolecular condensates paralogs |
| title | Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/β-catenin signaling |
| title_full | Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/β-catenin signaling |
| title_fullStr | Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/β-catenin signaling |
| title_full_unstemmed | Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/β-catenin signaling |
| title_short | Endogenous oligomer formation underlies DVL2 condensates and promotes Wnt/β-catenin signaling |
| title_sort | endogenous oligomer formation underlies dvl2 condensates and promotes wnt β catenin signaling |
| topic | dishevelled DVL2 Wnt signaling biomolecular condensates paralogs |
| url | https://elifesciences.org/articles/96841 |
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