ArticleMolecular and cellular biology2001
Conformational switch and role of phosphorylation in PAK activation.
Article in Molecular and cellular biology, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 105 citations in OpenAlex.
- p21-Activated Kinase (PAK) Group I-Targeting Inhibitors Promote the Dimeric Conformation in Live Cells.ACS chemical biology · 2026Article
- Modulating PAK1: Accessory Proteins as Promising Therapeutic Targets.Biomolecules · 2025Review
- Review
- Review
- Cdc42/Rac Interactive Binding Containing Effector Proteins in Unicellular Protozoans With Reference to Human Host: Locks of the Rho Signaling.Frontiers in genetics · 2022Review
- The significance of PAK4 in signaling and clinicopathology: A review.Open life sciences · 2022Review
- Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities.International journal of molecular sciences · 2021Review
- P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer.Theranostics · 2020Review
- Solution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited inThe Biochemical journal · 2019Article
- Article
- p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation.World journal of gastroenterology · 2018Review
- Melanoma-associated mutants within the serine-rich domain of PAK5 direct kinase activity to mitogenic pathways.Oncotarget · 2018Article
- A mutation in Nischarin causes otitis media via LIMK1 and NF-κB pathways.PLoS genetics · 2017Article
- Review
- Targeting PAK1.Biochemical Society transactions · 2017Review
- Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain.Journal of neurochemistry · 2015Article
- Structural insights into the intertwined dimer of fyn SH2.Protein science : a publication of the Protein Society · 2015Article
- The IQGAP-related protein DGAP1 mediates signaling to the actin cytoskeleton as an effector and a sequestrator of Rac1 GTPases.Cellular and molecular life sciences : CMLS · 2014Article
- P21 activated kinases: structure, regulation, and functions.Small GTPases · 2014Review
- PAK signalling during the development and progression of cancer.Nature reviews. Cancer · 2014Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
p21-activated protein kinases (PAKs) are involved in signal transduction processes initiating a variety of biological responses. They become activated by interaction with Rho-type small GTP-binding proteins Rac and Cdc42 in the GTP-bound conformation, thereby relieving the inhibition of the regulatory domain (RD) on the catalytic domain (CD). Here we report on the mechanism of activation and show that proteolytic digestion of PAK produces a heterodimeric RD-CD complex consisting of a regulatory fragment (residues 57 to 200) and a catalytic fragment (residues 201 to 491), which is active in the absence of Cdc42. Cdc42-GppNHp binds with low affinity (K(d) 0.6 microM) to intact kinase, whereas the affinity to the isolated regulatory fragment is much higher (K(d) 18 nM), suggesting that the difference in binding energy is used for the conformational change leading to activation. The full-length kinase, the isolated RD, and surprisingly also their complexes with Cdc42 behave as dimers on a gel filtration column. Cdc42-GppNHp interaction with the RD-CD complex is also of low affinity and does not dissociate the RD from the CD. After autophosphorylation of the kinase domain, Cdc42 binds with high (14 nM) affinity and dissociates the RD-CD complex. Assuming that the RD-CD complex mimics the interaction in native PAK, this indicates that the small G protein may not simply release the RD from the CD. It acts in a more subtle allosteric control mechanism to induce autophosphorylation, which in turn induces the release of the RD and thus full activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.