Key result
Cyclase-associated protein depolymerizes actin barbed ends, increasing formin residence time ~10-fold.
CAP functions as a processive depolymerase at both barbed and pointed ends of actin filaments, establishing it as a key player in actin dynamics.
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Hypothesis-generating for actin remodeling in cardiac cells; leaves open in vivo validation before any clinical relevance.
Cellular actin networks display distinct assembly and disassembly dynamics resulting from multicomponent reactions occurring primarily at the two ends and the sides of actin filaments [1-3]. While barbed ends are considered the hotspot of actin assembly [4], disassembly is thought to primarily occur via reactions on filament sides and pointed ends [3, 5-11]. Cyclase-associated protein (CAP) has emerged as the main protagonist of actin disassembly and remodeling - it collaborates with cofilin to increase pointed-end depolymerization by 300-fold [6, 7], promotes filament "coalescence" in presence of Abp1 [12], and accelerates nucleotide exchange to regenerate monomers for new rounds of assembly [13-15]. CAP has also been reported to enhance cofilin-mediated severing [16, 17], but these claims have since been challenged [7]. Using microfluidics-assisted three-color single-molecule imaging, we now reveal that CAP also has important functions at filament barbed ends. We reveal that CAP is a processive barbed-end depolymerase capable of tracking both ends of the filament. Each CAP binding event leads to removal of about 5,175 and 620 subunits from the barbed and pointed ends respectively. We find that the WH2 domain is essential, and the CARP domain is dispensable for barbed-end depolymerization. We show that CAP co-localizes with barbed-end bound formin and capping protein, in the process increasing residence time of formin by 10-fold and promoting dissociation of CP by 4-fold. Our barbed-end observations combined with previously reported activities of CAP at pointed ends and sides, firmly establish CAP as a key player in actin dynamics.
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Towsif et al. (2023) studied this question. Cyclase-associated protein (CAP) was evaluated on Actin filament depolymerization and interaction with formin and capping protein. Cyclase-associated protein acts as a processive barbed-end depolymerase, removing ~5,175 subunits per binding event, increasing formin residence time 10-fold, and promoting capping protein dissociation 4-fold.
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