Competitive displacement of cofilin can promote actin filament severing

Elam, W. Austin; Kang, Hyeran; Cruz, Enrique M. De La

doi:10.1016/j.bbrc.2013.07.109

Cited by 44 publications

(59 citation statements)

References 46 publications

(78 reference statements)

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“…Consistent with a functional ternary Aip1-cofilin-actin complex, Aip1 does not dissociate cofilin and enhances severing at all cofilin occupancies (62). However, a different study (63) favors an alternate mechanism (64) in which Aip1 simply competes with cofilin, dissociating it from actin and introducing additional boundaries where severing can occur.…”

Section: Filament Fragmentationmentioning

confidence: 87%

Actin Mechanics and Fragmentation

Cruz

Gardel

2015

Journal of Biological Chemistry

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Cell physiological processes require the regulation and coordination of both mechanical and dynamical properties of the actin cytoskeleton. Here we review recent advances in understanding the mechanical properties and stability of actin filaments and how these properties are manifested at larger (network) length scales. We discuss how forces can influence local biochemical interactions, resulting in the formation of mechanically sensitive dynamic steady states. Understanding the regulation of such force-activated chemistries and dynamic steady states reflects an important challenge for future work that will provide valuable insights as to how the actin cytoskeleton engenders mechanoresponsiveness of living cells.

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Section: Filament Fragmentationmentioning

confidence: 87%

Actin Mechanics and Fragmentation

Cruz

Gardel

2015

Journal of Biological Chemistry

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“…In response to the stimuli, the kinases phosphorylate, whereas the phosphatases dephosphorylate Cofilin to control its interaction with actin for optimal severing activity to regulate the dynamics of actin cytoskeleton (14,44). In addition, some small molecules or actin-binding protein ligands can competitively displace Cofilin to decrease the binding density of this protein on F-actin into a range that favors severing activity (43,44). These results suggest that the regulation of Cofilin binding to F-actin is controlled by multiple mechanisms and might be the primary process for Cofilin severing activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

Trp-Asp (WD) Repeat Domain 1 Is Essential for Mouse Peri-implantation Development and Regulates Cofilin Phosphorylation

Xiao

Wan

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangTrp-Asp (WD) repeat domain 1 (WDR1) is a highly conserved actin-binding protein across all eukaryotes and is involved in numerous actin-based processes by accelerating Cofilin severing actin filament. However, the function and the mechanism of WDR1 in mammalian early development are still largely unclear. We now report that WDR1 is essential for mouse periimplantation development and regulates Cofilin phosphorylation in mouse cells. The disruption of maternal WDR1 does not obviously affect ovulation and female fertility. However, depletion of zygotic WDR1 results in embryonic lethality at the periimplantation stage. In WDR1 knock-out cells, we found that WDR1 regulates Cofilin phosphorylation. Interestingly, WDR1 is overdosed to regulate Cofilin phosphorylation in mouse cells. Furthermore, we showed that WDR1 interacts with Lim domain kinase 1 (LIMK1), a well known phosphorylation kinase of Cofilin. Altogether, our results provide new insights into the role and mechanism of WDR1 in physiological conditions.The actin cytoskeleton is a highly dynamic structure that regulates cell motility, adhesion, division, and growth and has a fundamental function in embryonic development (1-3). In physiological conditions, actin filaments are continually assembled and disassembled in response to varied cellular activities (4, 5). The dynamics of F-actin is well orchestrated by a large number of actin-binding proteins (5, 6). Actin-depolymerizing factor Cofilin plays critical roles in the modulation of actin cytoskeleton dynamics (7). In vitro, Cofilin severs actin filament at low concentrations, whereas it fully decorates actin filaments and suppresses the severing activity at high concentrations (8, 9). In addition, Cofilin severing F-actin is not explained well for how the filaments of actin cytoskeleton can be rapidly disassembled in physiological conditions (4). Thus, the function of Cofilin in actin dynamics depends not only on its relative concentration to actin, but also on other regulatory proteins in vivo. Dysfunction of these regulating proteins results in aberrant actin cytoskeleton in various cellular and developmental processes (10 -12).Cofilin directly binds with actin to function as a regulator of the actin dynamics (13). However, the phosphorylation of Cofilin at Ser-3 blocks its binding site to actin (14, 15). Thus, the activity of Cofilin is controlled by phosphorylation and dephosphorylation processes, which are regulated by cascade reactions of several protein kinases and phosphatases. Lim domain kinases (LIMKs) 4 and testis-specific protein kinases (TESKs) are responsible for the phosphorylation of Cofilin, whereas slingshot (SSH) family protein phosphatases and pyridoxal phosphatase (PDXP) catalyze the dephosphorylation reaction (16 -20). These kinases and phosphatases are also regulated by their phosphorylation or localization in cytoplasm to maintain the level of Cofilin phosphorylation in response to extracellular stimuli (21-23).The activity of Cofilin on actin disassembly is gr...

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“…In the phalloidin competition experiment, 2 μM Alexa-488-labeled actin filaments equilibrated with cofilin and phalloidin were diluted in KMI 6.8 buffer containing cofilin, yielding a range of binding densities and phalloidin (31). In the gelsolin severing experiment, preformed Alexa-488-labeled yeast actin filaments were equilibrated with gelsolin (at a molar ratio of 1:370) in buffer B [10 mM Tris·Cl (pH 7.4), 50 mM KCl, 0.2 mM MgCl 2 , 0.1 mM ATP, 0.5 mM DTT, and 0.2 mM CaCl 2 ] at room temperature for 5-10 min, followed by dilution in buffer B for imaging (45).…”

Section: Methodsmentioning

confidence: 99%

“…Other filament binding proteins (e.g., tropomyosin and myosin) that bind at or near the stiffness site could potentially disrupt site geometry and cation occupancy (21). This may seem at variance with the observed stiffening effects of these proteins (29)(30)(31). However, this could be realized if cation-dependent interactions are replaced with more stabilizing protein-protein interactions (e.g., directly binding adjacent filament subunits).…”

Section: Significancementioning

confidence: 99%

Site-specific cation release drives actin filament severing by vertebrate cofilin

Kang

Bradley

Cao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Actin polymerization powers the directed motility of eukaryotic cells. Sustained motility requires rapid filament turnover and subunit recycling. The essential regulatory protein cofilin accelerates network remodeling by severing actin filaments and increasing the concentration of ends available for elongation and subunit exchange. Although cofilin effects on actin filament assembly dynamics have been extensively studied, the molecular mechanism of cofilin-induced filament severing is not understood. Here we demonstrate that actin filament severing by vertebrate cofilin is driven by the linked dissociation of a single cation that controls filament structure and mechanical properties. Vertebrate cofilin only weakly severs Saccharomyces cerevisiae actin filaments lacking this "stiffness cation" unless a stiffness cation-binding site is engineered into the actin molecule. Moreover, vertebrate cofilin rescues the viability of a S. cerevisiae cofilin deletion mutant only when the stiffness cation site is simultaneously introduced into actin, demonstrating that filament severing is the essential function of cofilin in cells. This work reveals that site-specific interactions with cations serve a key regulatory function in actin filament fragmentation and dynamics.cytoskeleton | persistence length | mechanics | electron cryomicroscopy A ctin polymerization powers the directed motility of eukaryotic cells and some pathogenic bacteria (1-3). Actin assembly also plays critical roles in endocytosis, cytokinesis, and establishment of cell polarity. Sustained motility requires filament disassembly and subunit recycling. The essential regulatory protein cofilin severs actin filaments (4-6), which accelerates actin network reorganization by increasing the concentration of filament ends available for subunit exchange (7).Cofilin binding alters the structure and mechanical properties of filaments, which effectively introduces local "defects" that compromise filament integrity and promote severing (5). Filaments with bound cofilin have altered twist (8, 9) and are more compliant in both bending and twisting than bare filaments (10-13). It has been suggested that deformations in filament shape promote fragmentation at or near regions of topological and mechanical discontinuities, such as boundaries between bare and cofilin-decorated segments along partially decorated filaments (5,12,(14)(15)(16)(17)(18).Cations modulate actin filament structure and mechanical properties (19) and cofilin dissociates filament-associated cations (20), leading us to hypothesize that cation-binding interactions regulate filament severing by cofilin. Cations bind filaments at two discrete and specific sites positioned between adjacent subunits along the long-pitch helix of the filament (19, 21). These cation binding sites are referred to as "polymerization" and "stiffness" sites based on their roles in filament assembly and mechanics, respectively. These discrete sites bind both monovalent and divalent cations with a range of affinities (low millimolar f...

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Competitive displacement of cofilin can promote actin filament severing

Cited by 44 publications

References 46 publications

Actin Mechanics and Fragmentation

Actin Mechanics and Fragmentation

Trp-Asp (WD) Repeat Domain 1 Is Essential for Mouse Peri-implantation Development and Regulates Cofilin Phosphorylation

Site-specific cation release drives actin filament severing by vertebrate cofilin

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