Cyclase-Associated Protein Dynamics in Actin Regulation

Cyclase-associated proteins (CAPs) are conserved multidomain regulators that orchestrate the continuous remodelling of the actin cytoskeleton. By binding both globular (G-actin) and filamentous actin (F-actin), CAPs serve as molecular facilitators of actin monomer recycling and filament turnover. At filament pointed ends, CAP synergises with cofilin to accelerate depolymerisation through destabilisation of terminal subunit interfaces and rapid monomer release. Concurrently, CAP catalyses nucleotide exchange on ADP-actin monomers to recharge them with ATP, rendering them assembly-competent. Beyond pointed-end disassembly, CAP interacts via its WH2 and CARP domains with barbed ends, displacing formins and attenuating filament elongation. This dual-end activity positions CAP as a central hub for coordinating severing, depolymerisation, monomer re-charging and filament growth inhibition. Such dynamic control underpins key cellular processes including morphogenesis, motility, endocytosis and synaptic plasticity. Moreover, dysregulation of CAP function has been linked to cardiac conduction defects, neurodevelopmental disorders and cancer cell invasion, highlighting its global significance and potential as a therapeutic target.

Research from Nature Portfolio

Seminal structural work has elucidated the mechanism by which CAP catalyses nucleotide exchange on actin monomers. A high-resolution structure of the CAP–actin complex revealed that the C-terminal β-sheet domain of CAP forms a sandwich-like interface with ADP-actin, positioning key residues to destabilise bound nucleotide and promote its release. This finding established CAP as the dedicated monomer re-charging factor essential for sustaining rapid filament assembly cycles.

Complementary studies have defined the synergy between CAP and cofilin in driving pointed-end depolymerisation. Single-molecule and microfluidics-assisted imaging showed that hexameric CAP molecules bind cooperatively to cofilin-decorated filaments, processively stripping subunits at rates hundreds of times faster than spontaneous disassembly. These experiments cemented a model in which CAP contacts terminal actin subunits to destabilise filament architecture and recycle both monomer and cofilin for subsequent turnover.

Cyclase-Associated Protein Dynamics in Actin Regulation publication trend

The graph below shows the total number of articles in cyclase-associated protein dynamics in actin regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Cyclase-associated protein (CAP): A conserved actin-binding protein with distinct domains for monomer re-charging and filament end regulation.

F-actin: Filamentous polymer of actin subunits forming dynamic cytoskeletal structures.

G-actin: Globular actin monomer that assembles into F-actin upon ATP binding.

Cofilin: Actin-binding protein that severs and depolymerises filaments by binding along the filament core.

Pointed end: The slower-growing or disassembling end of an actin filament, where CAP-cofilin synergy acts.

Barbed end: The fast-growing end of an actin filament, targeted by CAP to inhibit elongation and displace formins.

WH2 domain: A short actin-monomer–binding motif within CAP that contributes to end-specific interactions.

References

1. Cyclase-associated protein (CAP) inhibits inverted formin 2 (INF2) to induce dendritic spine maturation. Cellular and Molecular Life Sciences (2024).
2. Cyclase-associated protein interacts with actin filament barbed ends to promote depolymerization and formin displacement. Journal of Biological Chemistry (2023).
3. Mechanism of synergistic actin filament pointed end depolymerization by cyclase-associated protein and cofilin. Nature Communications (2019).
4. Structural basis of actin monomer re-charging by cyclase-associated protein. Nature Communications (2018).
5. CAPt’n of Actin Dynamics: Recent Advances in the Molecular, Developmental and Physiological Functions of Cyclase-Associated Protein (CAP). Frontiers in Cell and Developmental Biology (2020).
6. The Cytoskeletal Protein Cyclase-Associated Protein 1 (CAP1) in Breast Cancer: Context-Dependent Roles in Both the Invasiveness and Proliferation of Cancer Cells and Underlying Cell Signals. International Journal of Molecular Sciences (2019).
7. CAP2 in cardiac conduction, sudden cardiac death and eye development. Scientific Reports (2015).