Stochastic machines as a colocalization mechanism for scaffold protein function
Open accessAbstract
The axis inhibition (Axin) scaffold protein colocalizes β‐catenin, casein kinase Iα, and glycogen synthetase kinase 3β by their binding to Axin's long intrinsically disordered region, thereby yielding structured domains with flexible linkers. This complex leads to the phosphorylation of β‐catenin, marking it for destruction. Fusing proteins with flexible linkers vastly accelerates chemical interactions between them by their colocalization. Here we propose that the complex works by random movements of a “stochastic machine,” not by coordinated conformational changes. This non‐covalent, modular assembly process allows the various molecular machine components to be used in multiple processes.
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Prior to Wnt signaling, the transcription factor β-catenin is maintained at low levels by the β-catenin destruction complex, an assembly of the 852 residue mostly disordered scaffold protein axin, the 2,843 residue massively disordered protein APC, and the three mostly structured proteins β-catenin, CKI-a, and GSK3b.
“Prior to Wnt signaling, the transcription factor β-catenin is maintained at low levels by the β-catenin destruction complex, which is an assembly of the 852 residue mostly disordered scaffold protein axin, the 2,843 residue massively disordered protein adenomatous polyposis coli (APC), and the three mostly structured proteins β-catenin, casein kinase Ia (CKI-a), and glycogen synthetase kinase 3b (”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [259]
The destruction complex works by random movements of a "stochastic machine," not by cooperative conformational changes.
“Thus, the destruction complex works by random movements of a ‘‘stochastic machine,’’ not by cooperative conformational changes [259].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [259]
β-catenin proteins undergo proteasomal destruction, which is greatly accelerated by the presence of IDRs in addition to the bound ubiquitin signal.
“Next, the β-catenin proteins undergo proteasomal destruction [259, 260], which is greatly accelerated by the presence of IDRs in addition to the bound ubiquitin signal [262].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [259]
Proteins bind heparin via intrinsically disordered sequences rich in lysine and arginine.
“Proteins bind heparin via intrinsically disordered sequences rich in lysine and arginine [259].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [259]
The affinity of growth factors/cytokines for heparin correlates with the percentage of disordered residues in heparin-binding sites.
“The affinity of growth factors/cytokines for heparin correlates with the percentage of disordered residues in heparin-binding sites [259].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [259]
These experiments provide strong experimental validation of the stochastic machine model.
“These experiments provide strong experimental validation of the stochastic machine model [259].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [259]
The two kinases phosphorylate residues within a long IDR at β-catenin's amino terminus.
“The two kinases phosphorylate residues within a long IDR at β-catenin’s amino terminus [259, 260].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [259]
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References 39 · Cited by 47
- Authors
- Xue, B., Romero, P. R., Noutsou, M., Maurice, M. M., Rüdiger, S. G. D., William, A. M., Mizianty, M. J., Kurgan, L., Uversky, V. N., & Dunker, A. K.
- Affiliations
- University of South Florida (US)
- Indiana University Indianapolis (US)
- University Medical Center Utrecht (NL)
- Utrecht University (NL)
- University of Alberta (CA)
- Russian Academy of Sciences (RU)
- Corresponding author
- Dunker, A. Keith
- ORCID
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2013-04-18
- Volume
- 587
- Issue
- 11
- Pages
- 1587-1591
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- PMC
- PMC4141485
- OpenAlex
- W2123095375
- Cited by
- 47
- References
- 39
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 7 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 3 · 2014: 5 · 2013: 2
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Digital Commons - University of South Florida (University of South Florida) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- National Institute of Health (R01 LM007688-01A1)
- Programs of the Russian Academy of Sciences (GM071714-01A2)
- IUPUI Signature Centers Initiative
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Axin, Wnt signaling, β-catenin phosphorylation, glycogen synthase kinase-3β, intrinsically disordered regions, protein colocalization, protein complex formation, flexible linkers, scaffold proteins
- MeSH terms
- Allosteric Regulation, Humans, Models, Molecular, Phosphorylation, Protein Processing, Post-Translational, Stochastic Processes, Protein Structure, Quaternary, Protein Transport, Casein Kinase I, beta Catenin, Proteolysis, Wnt Signaling Pathway, Axin Signaling Complex
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