title: Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded.
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.
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Noutsou
authors.forename: Afonso M S
authors.initials: AM
authors.lastname: Duarte
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Anvarian
authors.forename: Tatiana
authors.initials: T
authors.lastname: Didenko
authors.forename: David P
authors.initials: DP
authors.lastname: Minde
authors.forename: Ineke
authors.initials: I
authors.lastname: Kuper
authors.forename: Isabel
authors.initials: I
authors.lastname: de Ridder
authors.forename: Christina
authors.initials: C
authors.lastname: Oikonomou
authors.forename: Assaf
authors.initials: A
authors.lastname: Friedler
authors.forename: Rolf
authors.initials: R
authors.lastname: Boelens
authors.forename: Stefan G D
authors.initials: SG
authors.lastname: Rüdiger
authors.forename: Madelon M
authors.initials: MM
authors.lastname: Maurice
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D060466:Axin Protein; D001665:Binding Sites; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D045170:Matrix Attachment Regions; D008958:Models, Molecular; D011485:Protein Binding; D058767:Protein Unfolding; D012097:Repressor Proteins / Q000737:chemistry*; D025521:Tumor Suppressor Proteins / Q000737:chemistry*; D051153:Wnt Proteins / Q000737:chemistry / Q000378:metabolism; D051176:beta Catenin / Q000737:chemistry
chemical_list: C555451:AXIN1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3