Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2
Wnt signaling is involved in embryo development and cancer. The binding between the DIX domains of Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1 is essential for Wnt/β-catenin signaling. Structural and biological studies have revealed that DIX domains are polymerized through head-to-tail interface...
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2024-10-01
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| author | Zehua Wen Lei Wang Shi-Wei Liu Hua-Jun Shawn Fan Jong-Won Song Ho-Jin Lee |
| author_facet | Zehua Wen Lei Wang Shi-Wei Liu Hua-Jun Shawn Fan Jong-Won Song Ho-Jin Lee |
| author_sort | Zehua Wen |
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| description | Wnt signaling is involved in embryo development and cancer. The binding between the DIX domains of Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1 is essential for Wnt/β-catenin signaling. Structural and biological studies have revealed that DIX domains are polymerized through head-to-tail interface interactions, which are indispensable for activating β-catenin Wnt signaling. Although different isoforms of Dvl and Axin proteins display both redundant and specific functions in Wnt signaling, the specificity of DIX-mediated interactions remains unclear due to technical challenges. Using AlphaFold2(AF2), we predict the structures of 6 homodimers and 22 heterodimers of DIX domains without templates and compare them with the reported X-ray complex structures. PRODIGY is used to calculate the binding affinities of these DIX complexes. Our results show that the Axin2 DIX homodimer has a stronger binding affinity than the Axin1 DIX homodimer. Among Dishevelled (Dvl) proteins, the binding affinity of the Dvl1 DIX homodimer is stronger than that of Dvl2 and Dvl3. The Coiled-coil-DIX1(Ccd1) DIX homodimer shows weaker binding than the Axin1 DIX homodimer. Generally, heterodimer interactions tend to be stronger than those of homodimers. Our findings provide insights into the mechanism of the Wnt signaling pathway and highlight the potential of AF2 and PRODIGY for studying protein–protein interactions in signaling pathways. |
| format | Article |
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| issn | 2073-4409 |
| language | English |
| publishDate | 2024-10-01 |
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| spelling | doaj-art-6fb1109bbb544c6aa1752dc0bf70155c2025-08-20T01:47:42ZengMDPI AGCells2073-44092024-10-011319164610.3390/cells13191646Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2Zehua Wen0Lei Wang1Shi-Wei Liu2Hua-Jun Shawn Fan3Jong-Won Song4Ho-Jin Lee5College of Chemical Engineering, Sichuan University of Science and Engineering, Zigong 64300, ChinaCollege of Chemical Engineering, Sichuan University of Science and Engineering, Zigong 64300, ChinaCollege of Chemical Engineering, Sichuan University of Science and Engineering, Zigong 64300, ChinaCollege of Chemical Engineering, Sichuan University of Science and Engineering, Zigong 64300, ChinaDepartment of Chemistry Education, Daegu University, Daegudae-ro 201, Gyeongsan-si 38453, Gyeongsangbuk-do, Republic of KoreaDivision of Natural & Mathematical Sciences, LeMoyne-Owen College, Memphis, TN 38126, USAWnt signaling is involved in embryo development and cancer. The binding between the DIX domains of Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1 is essential for Wnt/β-catenin signaling. Structural and biological studies have revealed that DIX domains are polymerized through head-to-tail interface interactions, which are indispensable for activating β-catenin Wnt signaling. Although different isoforms of Dvl and Axin proteins display both redundant and specific functions in Wnt signaling, the specificity of DIX-mediated interactions remains unclear due to technical challenges. Using AlphaFold2(AF2), we predict the structures of 6 homodimers and 22 heterodimers of DIX domains without templates and compare them with the reported X-ray complex structures. PRODIGY is used to calculate the binding affinities of these DIX complexes. Our results show that the Axin2 DIX homodimer has a stronger binding affinity than the Axin1 DIX homodimer. Among Dishevelled (Dvl) proteins, the binding affinity of the Dvl1 DIX homodimer is stronger than that of Dvl2 and Dvl3. The Coiled-coil-DIX1(Ccd1) DIX homodimer shows weaker binding than the Axin1 DIX homodimer. Generally, heterodimer interactions tend to be stronger than those of homodimers. Our findings provide insights into the mechanism of the Wnt signaling pathway and highlight the potential of AF2 and PRODIGY for studying protein–protein interactions in signaling pathways.https://www.mdpi.com/2073-4409/13/19/1646AlphaFold2PRODIGYDIXbinding affinityWnt signaling |
| spellingShingle | Zehua Wen Lei Wang Shi-Wei Liu Hua-Jun Shawn Fan Jong-Won Song Ho-Jin Lee Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2 Cells AlphaFold2 PRODIGY DIX binding affinity Wnt signaling |
| title | Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2 |
| title_full | Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2 |
| title_fullStr | Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2 |
| title_full_unstemmed | Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2 |
| title_short | Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2 |
| title_sort | exploring dix dix homo and hetero oligomers in wnt signaling with alphafold2 |
| topic | AlphaFold2 PRODIGY DIX binding affinity Wnt signaling |
| url | https://www.mdpi.com/2073-4409/13/19/1646 |
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