Structure and control of the actin regulatory WAVE complex
Open accessAbstract
Members of the Wiskott-Aldrich syndrome protein (WASP) family control cytoskeletal dynamics by promoting actin filament nucleation with the Arp2/3 complex. The WASP relative WAVE regulates lamellipodia formation within a 400-kilodalton, hetero-pentameric WAVE regulatory complex (WRC). The WRC is inactive towards the Arp2/3 complex, but can be stimulated by the Rac GTPase, kinases and phosphatidylinositols. Here we report the 2.3-ångstrom crystal structure of the WRC and complementary mechanistic analyses. The structure shows that the activity-bearing VCA motif of WAVE is sequestered by a combination of intramolecular and intermolecular contacts within the WRC. Rac and kinases appear to destabilize a WRC element that is necessary for VCA sequestration, suggesting the way in which these signals stimulate WRC activity towards the Arp2/3 complex. The spatial proximity of the Rac binding site and the large basic surface of the WRC suggests how the GTPase and phospholipids could cooperatively recruit the complex to membranes.
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Rac1 binding results in dissociation of CYFIP1 from the WAVE regulatory complex, allowing WAVE to activate Arp2/3 and enabling de novo F-actin assembly.
“Rac1 binding results in dissociation of CYFIP1 from the WAVE regulatory complex, allowing WAVE to activate the actin nucleator Arp2/3 and subsequently enabling de novo F-actin assembly.30,31”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [31]
The ‘Activation by Rac’ section (page not provided) says Rac1 activates the WRC without disrupting the complex’s integrity, contrary to the claimed dissociation of CYFIP1 (Sra1). It proposes release of WAVE’s VCA motif instead. The Abstract supports the downstream Arp2/3-mediated actin-assembly point, but not the stated dissociation mechanism. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe main role of CYFIP1 in the WAVE regulatory complex is to maintain the complex in an inhibited state until Rac1 binds CYFIP1.
“The main role of CYFIP1 in this complex is to maintain the WAVE regulatory complex in an inhibited state until the small GTPase Rac1, once activated, binds CYFIP1.”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [31]
The ‘Mechanism of WRC inhibition’ section shows that Sra1/CYFIP1 helps sequester WAVE’s activity-bearing VCA motif, and ‘Activation by Rac’ identifies an Sra1 surface involved in Rac1 binding. But the paper presents release of that inhibition by Rac1 as a proposed mechanism, not a certainty, and also describes activation by kinases and phosphatidylinositols. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe segregation of CYFIP1 into the two complexes relies on alternative CYFIP1 conformations: a planar one needed for the WRC and a more globular one for interaction with eIF4E.
“The segregation into the two complexes relies on alternative CYFIP1 conformations, a planar one needed for the WRC (Chen et al., 2010), and a more globular one for the interaction with eIF4E.”
From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Chen et al., 2010
The Overall structure of the WRC section describes Sra1/CYFIP1 as part of an elongated structural platform in the WRC. The Discussion suggests that Sra1 may partition between the WRC and a separate state that binds eIF4E, but it does not establish that segregation relies on alternative CYFIP1 conformations or that a planar conformation is required for the WRC. No page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn the WRC crystal structure, NCKAP1 interacts with CYFIP1 over a large surface, and Lys743, critical for eIF4E binding, is covered by NCKAP1 and not accessible to solvent when CYFIP1 is in the WRC.
“According to the crystal structure of the WRC that includes CYFIP1 (Chen et al., 2010), NCKAP1 interacts with CYFIP1 over a large surface (Figure 1A, upper panel); the lysine critical for the binding to eIF4E (Lys743) (Napoli et al., 2008) is covered by NCKAP1 and therefore is not accessible to solvent when CYFIP1 is in the WRC (Figure 1A, bottom panels, Table S1).”
From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Chen et al., 2010
The Overall structure of the WRC section says Sra1/CYFIP1 and Nap1/NCKAP1 interact extensively. The Discussion says the proposed mode of eIF4E binding is incompatible with the WRC structure. Our copy does not identify Lys743 or state that NCKAP1 covers that residue and makes it inaccessible to solvent. (LLM, conf=0.84)
Experimental — accuracy not yet measuredStructural studies of the WAVE complex in vitro have used a recombinant WAVE complex containing mini-WAVE, which lacks the proline-rich region due to the disordered nature of this region and difficulty in crystallization.
“Structural studies of the WAVE complex in vitro have used a recombinant WAVE complex containing mini-WAVE21,28,30,172, which lacks the proline-rich region due to the disordered nature of this region and difficulty in crystallization21.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [21]
In “Overall structure of the WRC” (page unavailable), the paper says it replaced WAVE1’s proline-rich region with a linker and removed Abi2’s proline-rich region to facilitate crystallization of the miniWRC. The passage does not say that disorder in the proline-rich region was the reason for those changes. (LLM, conf=0.87)
Experimental — accuracy not yet measured
CYFIP1 negatively regulates local actin filament assembly.
“CYFIP1 negatively regulates local actin filament assembly, suggesting that actin dynamics may be altered in Cyfip1+/− dendritic spines.”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [31]
Rac1 signaling can activate the WRC through CYFIP1.
“In particular, the Rac1 signaling can activate the WRC through CYFIP1 (Chen et al., 2010, Eden et al., 2002, Kobayashi et al., 1998, Schenck et al., 2003, Steffen et al., 2004).”
From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Chen et al., 2010
The availability of the WCA region of WAVE for ARP2/3 activation is hindered by multiple interactions with both CYFIP and the "meander" region of WAVE.
“The availability of the WCA region of WAVE for ARP2/3 activation is hindered by multiple interactions with both CYFIP and the “meander” region of WAVE21 (Fig. 2).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [21]
WAVE proteins exist as heteropentameric complexes together with regulatory proteins including CYFIP, NCKAP, ABI and BRK1 (specifically NCKAP1/1L, CYFIP1/2, ABI1/2/3, and BRK1).
“WAVE proteins exist as heteropentameric complexes together with regulatory proteins, including CYFIP, NCKAP, ABI and BRK1.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [21]
ABL tyrosine kinase phosphorylates Tyr151 of WAVE1, Tyr150 of WAVE2 or Tyr151 of WAVE3, and this phosphorylation is suggested to interfere with the interaction between the WAVE meander region and CYFIP, releasing the WCA region for ARP2/3 activation.
“The ABL tyrosine kinase phosphorylates Tyr151 of WAVE1, Tyr150 of WAVE2 or Tyr151 of WAVE337,38, and this phosphorylation is suggested to interfere with the interaction between the WAVE meander region and CYFIP, releasing the WCA region for ARP2/3 activation21 (Figs. 2 and 3a–c).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [21]
Differential RNA expression governs which isoform will be incorporated in the WRC.
“Differential RNA expression governs which isoform will be incorporated in the WRC [14].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [14]
The ‘Overall structure of the WRC’ section identifies WAVE1 and Abi2 in the assembled complex, and describes experiments replacing WAVE2 in HeLa cells. Neither that section nor the passages returned for ‘RNA expression’ and ‘isoforms differential expression’ addresses whether differential RNA expression determines which isoform is incorporated. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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Flagged first, then by citations
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- Authors
- Chen, Z., Borek, D., Padrick, S. B., Gomez, T. S., Metlagel, Z., Ismail, A. M., Umetani, J., Billadeau, D. D., Otwinowski, Z., & Rosen, M. K.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Mayo Clinic (US)
- Corresponding author
- Rosen, Michael K.
- ORCID
- Venue
- Nature
- Published
- 2010-11
- Volume
- 468
- Issue
- 7323
- Pages
- 533-538
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3085272
- OpenAlex
- W2066953183
- Cited by
- 500
- References
- 2
- Citations by year
- 2026: 21 · 2025: 28 · 2024: 23 · 2023: 31 · 2022: 40 · 2021: 41 · 2020: 47 · 2019: 44 · 2018: 32 · 2017: 35 · 2016: 29 · 2015: 24 · 2014: 29 · 2013: 30 · 2012: 30
- FWCI
- 10.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research Institute
- National Institutes of Health
- National Institute of General Medical Sciences (F32GM069179, R01GM053163, R01GM056322, 1F32-GM06917902)
- National Institute of Allergy and Infectious Diseases (T32AI007047, AI07047, R01AI065474)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- WAVE regulatory complex, Arp2/3 complex, actin filament nucleation, lamellipodia formation, Rac GTPase, crystal structure, cell motility, cytoskeletal dynamics, membrane recruitment, phosphatidylinositol, kinase activation
- MeSH terms
- Actins, Animals, HeLa Cells, Humans, Insecta, Models, Molecular, Phosphorylation, rac1 GTP-Binding Protein, Protein Structure, Quaternary, Wiskott-Aldrich Syndrome Protein Family
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