Mechanism of synergistic actin filament pointed end depolymerization by cyclase-associated protein and cofilin

Abstract

The ability of cells to generate forces through actin filament turnover was an early adaptation in evolution. While much is known about how actin filaments grow, mechanisms of their disassembly are incompletely understood. The best-characterized actin disassembly factors are the cofilin family proteins, which increase cytoskeletal dynamics by severing actin filaments. However, the mechanism by which severed actin filaments are recycled back to monomeric form has remained enigmatic. We report that cyclase-associated-protein (CAP) works in synergy with cofilin to accelerate actin filament depolymerization by nearly 100-fold. Structural work uncovers the molecular mechanism by which CAP interacts with actin filament pointed end to destabilize the interface between terminal actin subunits, and subsequently recycles the newly-depolymerized actin monomer for the next round of filament assembly. These findings establish CAP as a molecular machine promoting rapid actin filament depolymerization and monomer recycling, and explain why CAP is critical for actin-dependent processes in all eukaryotes.

Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure

“…Cyclase-associated proteins (CAP) can control filament turnover by recycling actin monomers and severing actin filaments [67]. In particular, it has been shown that the N-terminal region of the yeast homolog Svr2/CAP is responsible for the role that CAP plays in synergy with cofilin to accelerate actin filament depolymerization [68][69][70][71]. In mammals, two CAP homologs are expressed: CAP1 shows a wide tissue distribution, whereas CAP2 is primarily present in brain, heart, and skeletal muscle, skin, and testis [72], suggesting that these proteins have distinct functional roles.…”

Actin filament oxidation by MICAL1 suppresses protections from cofilin-induced disassembly

“…Nevertheless, on its own, ADF/cofilin cannot account for the very rapid turnover of filaments observed in cells. It can be assisted by various other ABPs, such as Cyclase Associated Protein which accelerates the pointed end depolymerization of cofilin-decorated filaments (Kotila et al, 2019;Shekhar et al, 2019).…”

CAP1 and cofilin1 cooperate in neuronal actin dynamics, growth cone function and neuron connectivity

“…While CAPs have been recognized as ABPs almost two decades ago (Balcer et al, 2003;Bertling et al, 2004;Freeman and Field, 2000;Hubberstey and Mottillo, 2002), significant progress in their molecular functions has been achieved just recently (Jansen et al, 2014;Johnston et al, 2015;Kotila et al, 2018;Kotila et al, 2019;Mu et al, 2019;Shekhar et al, 2019). These studies, which either exploited recombinant proteins or have been performed in yeast or non-neuronal cell lines, implicated CAP1 and CAP2, but also their yeast homolog Srv2 (suppressor of Ras2-Val19) in actin dynamics.…”

“…Together, our data identified HFD to be relevant for CAP1 in growth cones. Since previous studies revealed an interaction of HFD with ADF/cofilin-actin-complexes (Kotila et al, 2019;Shekhar et al, 2019), we hypothesized that CAP1 interacts with ADF/cofilin in growth cones.…”

“…Although numerous ABPs including the actin depolymerizing protein cofilin1 have been implicated in growth cone motility, our knowledge about actin regulatory mechanisms in growth cones is still fragmented (Dent et al, 2011;Gomez and Letourneau, 2014;Omotade et al, 2017;Vitriol and Zheng, 2012). By exploiting recombinant proteins and yeast mutant strains, recent studies implicated cyclase-associated protein (CAP) in both F-actin disassembly and nucleotide exchange on G-actin (Johnston et al, 2015;Kotila et al, 2018;Kotila et al, 2019;Shekhar et al, 2019). Unlike yeast, mammals possess two CAP family members, CAP1 and CAP2, with different expression patterns.…”