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  • Review Article
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Capping protein regulators fine-tune actin assembly dynamics

Nature Reviews Molecular Cell Biology volume 15, pages 677–689 (2014)Cite this article

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An Erratum to this article was published on 19 September 2014

This article has been updated

Key Points

  • Capping protein (CP) is a major regulator of actin assembly dynamics via the capping of actin filament barbed ends. The capping activity of CP can be regulated by a number of different proteins and phospholipids in various ways, some direct and others indirect.

  • The capping protein interacting (CPI) motif is a 30-amino acid region necessary and sufficient to bind and inhibit CP. This motif is found in a set of unrelated proteins, many of which are involved in membrane interactions.

  • CARMIL (capping protein, ARP2/3 and myosin I linker) family proteins contain a CPI motif, and they also contain a separate CARMIL-specific interacting (CSI) motif. In CARMIL, the CPI motif is necessary for distinct cellular functions, such as macropinocytosis.

  • The CPI and CSI motifs are unstructured in the unbound state, but they adopt a specific structure when they bind to CP, applying themselves to the surface of CP. The CPI and CSI motifs decrease the actin capping activity of CP via an allosteric mechanism.

  • The complex of a CPI motif-containing protein with CP retains a low level of capping activity, which raises the possibility that CPI motif-containing proteins may target CP to certain cellular locations, in addition to, or as an alternative to, simply decreasing the capping activity.

  • Vertebrates have three distinct conserved CARMIL genes, which seem to have distinct functions in cells. Of note, CARMIL2 localizes with vimentin filaments, representing a potential novel link between the actin and intermediate filament cytoskeleton systems.

Abstract

Capping protein (CP) binds the fast growing barbed end of the actin filament and regulates actin assembly by blocking the addition and loss of actin subunits. Recent studies provide new insights into how CP and barbed-end capping are regulated. Filament elongation factors, such as formins and ENA/VASP (enabled/vasodilator-stimulated phosphoprotein), indirectly regulate CP by competing with CP for binding to the barbed end, whereas other molecules, including V-1 and phospholipids, directly bind to CP and sterically block its interaction with the filament. In addition, a diverse and unrelated group of proteins interact with CP through a conserved 'capping protein interaction' (CPI) motif. These proteins, including CARMIL (capping protein, ARP2/3 and myosin I linker), CD2AP (CD2-associated protein) and the WASH (WASP and SCAR homologue) complex subunit FAM21, recruit CP to specific subcellular locations and modulate its actin-capping activity via allosteric effects.

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Figure 1: Capping protein regulates actin filament dynamics during several cellular processes.
Figure 2: Modes of capping protein inhibition.
Figure 3: CPI motif-containing proteins.
Figure 4: Cellular functions of CPI motif-containing proteins.

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Change history

  • 19 September 2014

    On page 684 of the above article, there was a mistake in Figure 3b: the PH domain of CARMIL preferentially binds to monophosphorylated membrane lipids rather than to PtdIns(3)P, PtdIns(3,4)P2 or PtdIns(3,4,5)P3. This has been corrected online. We apologize for any confusion caused to readers.

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Acknowledgements

The authors thank members of their laboratories for comments on the manuscript and contributions to the work discussed in this article. They also thank R. Cheney and R. Insall for comments on the manuscript. Work in the authors' laboratories and the writing of this manuscript was supported by National Institutes of Health (NIH) grants GM038542 and GM095509 (to J.A.C.) and GM073791 and MH087950 (to R.D.). M.E. was supported by NIH training grant 5T90DA02287104.

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Authors and Affiliations

  1. Department of Cell Biology and Physiology, Washington University, St. Louis, 63110, Missouri, USA

    Marc Edwards & John A. Cooper

  2. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Adam Zwolak & Roberto Dominguez

  3. Departments of Biology and Cell Biology, University of Virginia, Charlottesville, 22904, Virginia, USA

    Dorothy A. Schafer

  4. Department of Biomedical Engineering and Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, Michigan, USA

    David Sept

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PowerPoint slides

Glossary

Sarcomere Z-disks

The sarcomere is the basic unit of the contractile apparatus of striated muscle. The Z-disk is the structure at each end of the sarcomere to which the barbed ends of the actin-based thin filaments are anchored.

BAR-domain proteins

BAR (Bin–amphiphysin–Rvs) domains of proteins bind to membranes, sensing and inducing curvature. They have roles in membrane trafficking.

Thin filaments

The sarcomere contains thin filaments composed of actin and thick filaments composed of myosin. Their interaction and sliding causes contraction of the sarcomere and hence the muscle.

Cortical actin

Actin filaments that are located close to the plasma membrane. These filaments control the shape and movement of the plasma membrane, and they are often highly dynamic.

Macropinocytosis

Engulfment of extracellular fluid by ruffling and folding back of the plasma membrane. Highly dependent on dynamic actin assembly.

Vimentin

A protein that forms intermediate filaments in cells. Found in a wide range of cell types.

Retromer

A protein complex of endosomes that is involved in membrane receptor recycling.

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Edwards, M., Zwolak, A., Schafer, D. et al. Capping protein regulators fine-tune actin assembly dynamics. Nat Rev Mol Cell Biol 15, 677–689 (2014). https://doi.org/10.1038/nrm3869

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