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A Large-Scale Conformational Change Couples Membrane Recruitment to Cargo Binding in the AP2 Clathrin Adaptor Complex
Open accessAbstract
The AP2 adaptor complex (alpha, beta2, sigma2, and mu2 subunits) crosslinks the endocytic clathrin scaffold to PtdIns4,5P(2)-containing membranes and transmembrane protein cargo. In the "locked" cytosolic form, AP2's binding sites for the two endocytic motifs, YxxPhi on the C-terminal domain of mu2 (C-mu2) and [ED]xxxL[LI] on sigma2, are blocked by parts of beta2. Using protein crystallography, we show that AP2 undergoes a large conformational change in which C-mu2 relocates to an orthogonal face of the complex, simultaneously unblocking both cargo-binding sites; the previously unstructured mu2 linker becomes helical and binds back onto the complex. This structural rearrangement results in AP2's four PtdIns4,5P(2)- and two endocytic motif-binding sites becoming coplanar, facilitating their simultaneous interaction with PtdIns4,5P(2)/cargo-containing membranes. Using a range of biophysical techniques, we show that the endocytic cargo binding of AP2 is driven by its interaction with PtdIns4,5P(2)-containing membranes.
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Cites
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
Phaser crystallographic software
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Self-citationPHENIX : building new software for automated crystallographic structure determination
Adams, P. D., Grosse-Kunstleve, R. W., Hung, L.-W., Ioerger, T. R., McCoy, A. J., Moriarty, N. W., Read, R. J., Sacchettini, J. C., Sauter, N. K., & Terwilliger, T. C. (2002) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444902016657 · Cited by 4,361
Self-citationMolecular model for a complete clathrin lattice from electron cryomicroscopy
Fotin, A., Cheng, Y., Sliz, P., Grigorieff, N., Harrison, S. C., Kirchhausen, T., & Walz, T. (2004) · Nature · doi:10.1038/nature03079 · Cited by 541
Cited by
Mechanisms of clathrin-mediated endocytosis
Kaksonen, M., & Roux, A. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.132 · Cited by 1,698
Regulation of Small GTPases by GEFs, GAPs, and GDIs
Cherfils, J., & Zeghouf, M. (2013) · Physiological Reviews · doi:10.1152/physrev.00003.2012 · Cited by 1,245
Regulation of Clathrin-Mediated Endocytosis
Mettlen, M., Chen, P.-H., Srinivasan, S., Danuser, G., & Schmid, S. L. (2018) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-062917-012644 · Cited by 614
Saheki, Y., & De Camilli, P. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005645 · Cited by 457
Endocytosis and signaling: Cell logistics shape the eukaryotic cell plan
Sigismund, S., Confalonieri, S., Ciliberto, A., Polo, S., Scita, G., & Di Fiore, P. P. (2012) · Physiological Reviews · doi:10.1152/physrev.00005.2011 · Cited by 338
Metadata
- Authors
- Jackson, L. P., Kelly, B. T., McCoy, A. J., Gaffry, T., James, L. C., Collins, B. M., Höning, S., Evans, P. R., & Owen, D. J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 141
- Issue
- 7
- Pages
- 1220-1229
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2117679566
- Cited by
- 379
- References
- 4
- FWCI
- 11.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Jackson, L. P., Kelly, B. T., McCoy, A. J., Gaffry, T., James, L. C., Collins, B. M., Höning, S., Evans, P. R., & Owen, D. J. (2010). A Large-Scale Conformational Change Couples Membrane Recruitment to Cargo Binding in the AP2 Clathrin Adaptor Complex. Cell. https://doi.org/10.1016/j.cell.2010.05.006
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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