Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded

Maria Noutsou, Afonso M.S. Duarte, Zeinab Anvarian, Tatiana Didenko, David P. Minde, Ineke Kuper, Isabel De Ridder, Christina Oikonomou, Assaf Friedler, Rolf Boelens, Stefan G.D. Rüdiger, Madelon M. Maurice

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

The Wnt pathway tumor-suppressor protein Axin coordinates the formation of a critical multiprotein destruction complex that serves to downregulate β-catenin protein levels, thereby preventing target gene activation. Given the lack of structural information on some of the major functional parts of Axin, it remains unresolved how the recruitment and positioning of Wnt pathway kinases, such as glycogen synthase kinase 3β, are coordinated to bring about β-catenin phosphorylation. Using various biochemical and biophysical methods, we demonstrate here that the central region of Axin that is implicated in binding glycogen synthase kinase 3β and β-catenin is natively unfolded. Our results support a model in which the unfolded nature of these critical scaffolding regions in Axin facilitates dynamic interactions with a kinase and its substrate, which in turn act upon each other.

Original languageAmerican English
Pages (from-to)773-786
Number of pages14
JournalJournal of Molecular Biology
Volume405
Issue number3
DOIs
StatePublished - 21 Jan 2011

Bibliographical note

Funding Information:
This work was supported by the Dutch Cancer Society ( UU 2006-3508 ), the European Research Council ( European Research Council starting grant 242958 to M.M.M.), the Utrecht University (High Potential Grants to M.M.M. and S.G.D.R.), the European Union (Marie-Curie-Excellence Grant to S.G.D.R.), and the Netherlands Organization for Scientific Research NWO (VIDI career development grant to S.G.D.R.). A.F. was supported by European Research Council starting grant 203413 . We thank Jacques P. F. Doux and Tania Rutters-Meijneke (Biochemistry of Membranes, Bijvoet Center) for help with CD experiments.

Keywords

  • Axin
  • Wnt pathway
  • natively unfolded
  • scaffold
  • β-catenin degradation

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