4WIP

DIX domain of human Dvl2

Summary for 4WIP

• Entry DOI: 10.2210/pdb4wip/pdb
• Related: 3PZ8
• Descriptor: Segment polarity protein dishevelled homolog DVL-2, PENTAETHYLENE GLYCOL (3 entities in total)
• Functional Keywords: polymer signaling ubiquitin-like, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Peripheral membrane protein ; Cytoplasmic side : O14641
• Total number of polymer chains: 3
• Total formula weight: 33626.01

Authors

Fiedler, M.,Bienz, M.,Madrzak, J.,Chin, J.W. (deposition date: 2014-09-26, release date: 2015-05-13, Last modification date: 2024-05-08)

Primary citation

Madrzak, J.,Fiedler, M.,Johnson, C.M.,Ewan, R.,Knebel, A.,Bienz, M.,Chin, J.W.
Ubiquitination of the Dishevelled DIX domain blocks its head-to-tail polymerization.
Nat Commun, 6:6718-6718, 2015

PubMed Abstract: Dishevelled relays Wnt signals from the plasma membrane to different cytoplasmic effectors. Its signalling activity depends on its DIX domain, which undergoes head-to-tail polymerization to assemble signalosomes. The DIX domain is ubiquitinated in vivo at multiple lysines, which can be antagonized by various deubiquitinases (DUBs) including the CYLD tumour suppressor that attenuates Wnt signalling. Here, we generate milligram quantities of pure human Dvl2 DIX domain mono-ubiquitinated at two lysines (K54 and K58) by genetically encoded orthogonal protection with activated ligation (GOPAL), to investigate their effect on DIX polymerization. We show that the ubiquitination of DIX at K54 blocks its polymerization in solution, whereas DIX58-Ub remains oligomerization-competent. DUB profiling identified 28 DUBs that cleave DIX-ubiquitin conjugates, half of which prefer, or are specific for, DIX54-Ub, including Cezanne and CYLD. These DUBs thus have the potential to promote Dvl polymerization and signalosome formation, rather than antagonize it as previously thought for CYLD.

PubMed: 25907794
DOI: 10.1038/ncomms7718

Experimental method

X-RAY DIFFRACTION (2.691 Å)