A structural basis for the pH‐dependence of cofilin

Blondin, Laurence; Sapountzi, Vasilia; Maciver, Sutherland K.; Lagarrigue, Emeline; Benyamin, Yves; Roustan, Claude

doi:10.1046/j.1432-1033.2002.03101.x

Cited by 25 publications

(26 citation statements)

References 61 publications

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“…The structural basis for this regulation may be shifts in the position of the F-site (Pope et al, 2004) and/or a pH-dependent conformational change in the actin molecule (Zimmerle and Frieden, 1988), which is recognized by AC proteins (Blondin et al, 2002). As shown here PfADF1, which lacks the F-site, is not pH dependent in its actin monomer binding activity.…”

Section: Discussionmentioning

confidence: 90%

APlasmodiumActin-depolymerizing Factor That Binds Exclusively to Actin Monomers

Schüler

Mueller

Matuschewski

2005

MBoC

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ADF/cofilins (AC) are essential F-and G-actin binding proteins that modulate microfilament turnover. The genome of Plasmodium falciparum, the parasite causing malaria, contains two members of the AC family. Interestingly, P. falciparum ADF1 lacks the F-actin binding residues of the AC consensus. Reverse genetics in the rodent malaria model system suggest that ADF1 performs vital functions during the pathogenic red blood cell stages, whereas ADF2 is not present in these stages. We show that recombinant PfADF1 interacts with monomeric actin but does not bind to actin polymers. Although other AC proteins inhibit nucleotide exchange on monomeric actin, the Plasmodium ortholog stimulates nucleotide exchange. Thus, PfADF1 differs in its biochemical properties from previously known AC proteins and seems to promote turnover exclusively by interaction with actin monomers. These findings provide important insights into the low cytosolic abundance and unique turnover characteristics of actin polymers in parasites of the phylum Apicomplexa. INTRODUCTIONApicomplexan parasites are important human and animal pathogens. Their gliding motility is actin dependent and involves neither protrusive structures nor any changes in cell shape (Sibley, 2004). Gliding motility and host cell entry are initiated by surface receptor binding to substrate or host cell ligands (Russell and Sinden, 1981). Backward distribution of the receptor-ligand complexes then propel the parasite forward and into the host cell (Kappe et al., 2003;Kappe et al., 2004;Sibley, 2004;Soldati and Meissner, 2004). Thus, rather than inducing endocytosis and hijacking the host cell's force transducing systems, apicomplexans actively cross cell barriers and translocate into the host cytoplasm under simultaneous formation of a replication-competent organelle, the parasitophorous vacuole.Actin-dependent motility typically depends on the existence of polymers of actin (F-actin), either by interaction of F-actin with the motor protein myosin or through tightly regulated dynamic turnover of F-actin. Apicomplexan gliding motility and host cell invasion are inhibited by cytochalasins, suggesting that actin filaments of the parasite are required for these processes (Dobrowolski and Sibley, 1996). However, microfilaments cannot be visualized within the cytoplasm of parasites using either electron microscopy or fluorescent derivatives of the F-actin binding toxin phalloidin Gantt et al., 2000), presumably because parasite microfilaments are very short (Schmitz et al., 2005). The cell-permeable drug jasplakinolide induced local filament formation at the apical ends of motile parasites, but it did not give rise to actin polymers within the parasite cytosol (Shaw and Tilney, 1999), suggesting the existence of a highly efficient monomer-sequestering mechanism.Short microfilaments exist in the space between the parasite plasma membrane and the inner membrane complex, where they are thought to interact with transmembrane receptors on one hand and a myosin motor on the other hand (Kappe...

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Section: Discussionmentioning

confidence: 90%

APlasmodiumActin-depolymerizing Factor That Binds Exclusively to Actin Monomers

Schüler

Mueller

Matuschewski

2005

MBoC

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“…The overall slower F-actin shortening by cofilin at pH 6.8 than 7.8 has been attributed to either a combination of nucleation and depolymerization rates [Bonet et al, 2000;Blondin et al, 2002] or the reduced severing and depolymerization of filaments [Chen et al, 2004]. However, indirect assays of filament severing by ADF showed little, if any, pH-dependence of this process [Yeoh et al, 2002].…”

Section: Discussionmentioning

confidence: 99%

“…Although recent studies suggest a possible role of conformational changes in actin [Blondin et al, 2002] or cofilin [Pope et al, 2004] in the pH-sensitivity of F-actin depolymerization by cofilin, they have not examined the severing reaction itself. In this study, fluorescence microscopy observations of Gln 41 -TRC-labeled actin filaments enabled the direct monitoring of their severing.…”

Section: Discussionmentioning

confidence: 99%

Severing of F-actin by yeast cofilin is pH-independent

Pavlov

Mühlrád

Cooper

et al. 2006

Cell Motil. Cytoskeleton

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Cofilin plays an important role in actin turnover in cells by severing actin filaments and accelerating their depolymerization. The role of pH in the severing by cofilin was examined using fluorescence microscopy. To facilitate the imaging of actin filaments and to avoid the use of rhodamine phalloidin, which competes with cofilin, α-actin was labeled with tetramethylrhodamine cadaverine (TRC) at Gln 41 . The TRC-labeling inhibited actin treadmilling strongly, as measured by εATP release. Cofilin binding, detected via an increase in light scattering, and the subsequent conformational change in filament structure, as detected by TRC fluorescence decay, occurred 2-3 times faster at pH 6.8 than at pH 8.0. In contrast, actin filaments severing by cofilin was pH-independent. The pH-independent severing by cofilin was confirmed using actin labeled at Cys 374 with Oregon Green ® 488 maleimide. The depolymerization of actin by cofilin was faster at high pH.

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“…CAP Rescues Cofilin Function at Neutral pH-Cofilin function is highly sensitive to pH, and at neutral or acidic pH, cofilin loses all severing activity, although it can still bind actin (33,34). Cytosolic pH in many cell types is near neutral or even slightly acidic (35).…”

Section: Cofilin Coronin and Aip1 Are Insufficient To Disassemble Amentioning

confidence: 99%

Cyclase-associated Protein (CAP) Acts Directly on F-actin to Accelerate Cofilin-mediated Actin Severing across the Range of Physiological pH

Normoyle

Brieher

2012

Journal of Biological Chemistry

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Background: Cytosolic pH blocks actin disassembly in vitro.Results: CAP actively participates in actin disassembly, augmenting cofilin activity across the physiological pH range. Conclusion: CAP is an important actin disassembly factor necessary to drive actin turnover under physiological conditions. Significance: We identify a new mechanism through which CAP affects fast actin dynamics even at acidic pH values found in cells.

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A structural basis for the pH‐dependence of cofilin

Cited by 25 publications

References 61 publications

APlasmodiumActin-depolymerizing Factor That Binds Exclusively to Actin Monomers

APlasmodiumActin-depolymerizing Factor That Binds Exclusively to Actin Monomers

Severing of F-actin by yeast cofilin is pH-independent

Cyclase-associated Protein (CAP) Acts Directly on F-actin to Accelerate Cofilin-mediated Actin Severing across the Range of Physiological pH

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