Cofilin-induced unidirectional cooperative conformational changes in actin filaments revealed by high-speed atomic force microscopy

Ngo, Kien Xuan; Kodera, Noriyuki; Katayama, Eisaku; Ando, Toshio; Uyeda, Taro Q.P.

doi:10.7554/elife.04806

Cited by 125 publications

(174 citation statements)

References 72 publications

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“…Alternatively, this behavior could arise if severing occurred preferentially at the pointed-end side of the cluster, as reported (32,33). A third possible explanation would be a mechanism in which cofilin clusters grew asymmetrically and more rapidly in the pointed-end direction (8), such that clusters extended to the filament pointed end.…”

Section: Asymmetries In Boundary Polaritymentioning

confidence: 99%

“…Filament fragmentation occurs preferentially at boundaries between bare and cofilin-decorated segments (3,(5)(6)(7)(8), but the structural origins of this behavior have not been established. Our results suggest that subunits directly adjacent to the boundary adopt conformations distinct from those within bare and cofilin-decorated segments.…”

Section: Implications For Filament Severingmentioning

confidence: 99%

“…A recent AFM study (8) reported that cofilactin-like twist propagates >10 subunits into bare actin segments from the pointed end side of cofilin clusters. We observe no detectable longrange propagation of the cofilactin-like twist into the bare actin segment, or vice versa (i.e.…”

Section: Allosteric Effects Of Cofilin On Actin Filament Twistmentioning

confidence: 99%

“…In contrast, differential scanning calorimetric (13) and spectroscopic lifetime (15) measurements estimate allosteric propagation of changes in structure, stability, and/or dynamics over N > 100 subunits. More recently, a singlemolecule TIRF study measured positive cooperative binding interactions that propagated exponentially with a decay length of N ~24 subunits (18), and atomic force microscopic imaging directly observed a change in the crossover distance of N ~14 bare actin subunits towards the pointed-end side of the boundary, but no propagation in the bare actin subunits towards the barbedend side of the boundary (8).…”

mentioning

confidence: 99%

“…Members of the cofilin/ADF family of actin regulatory proteins (1,2) bind actin filaments cooperatively (3)(4)(5) and promote severing preferentially at and near junctions between bare and cofilin-decorated (cofilactin) segments (3,(5)(6)(7)(8), hereafter referred to as boundaries. Cofilin alters the average actin filament twist (9) and subunit tilt (10,11).…”

mentioning

confidence: 99%

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The actin filament twist changes abruptly at boundaries between bare and cofilin-decorated segments

Huehn

Cao

Elam

et al. 2018

Journal of Biological Chemistry

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Cofilin/ADF proteins are actin-remodeling proteins, essential for actin disassembly in various cellular processes, including cell division, intracellular transport, and motility. Cofilins bind actin filaments cooperatively and sever them preferentially at boundaries between bare and cofilin-decorated (cofilactin) segments. The cooperative binding to actin has been proposed to originate from conformational changes that propagate allosterically from clusters of bound cofilin to bare actin segments. Estimates of the lengths over which these cooperative conformational changes propagate vary dramatically, ranging from 2 to >100 subunits. Here, we present a general, structure-based method for detecting from cryo-EM micrographs small variations in filament geometry (i.e. twist) with single subunit precision. How these variations correlate with regulatory protein occupancy reveals how far allosteric, conformational changes propagate along filaments. We used this method to determine the effects of cofilin on the actin filament twist. Our results indicate that cofilin-induced changes in filament twist propagate only 1-2 subunits from the boundary into the bare actin segment, independently of the boundary polarity (i.e. irrespective of whether or not the bare actin segment flanks the pointed or barbed end side of the boundary) and the pyrene fluorophore labeling of actin. These observations indicate that the filament twist changes abruptly at boundaries between bare and cofilin-decorated segments, thereby constraining mechanistic models of cooperative actin filament interactions and severing by cofilin. The methods presented here extend the capability of cryo-EM to analyze biologically relevant deviations from helical symmetry in actin as well as other classes of linear polymers.

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Section: Asymmetries In Boundary Polaritymentioning

confidence: 99%

Section: Implications For Filament Severingmentioning

confidence: 99%

Section: Allosteric Effects Of Cofilin On Actin Filament Twistmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The actin filament twist changes abruptly at boundaries between bare and cofilin-decorated segments

Huehn

Cao

Elam

et al. 2018

Journal of Biological Chemistry

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Visualizing dynamic actin cross‐linking processes driven by the actin‐binding protein anillin

et al. 2019

Self Cite

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Anillin is a type of actin filament cross-linking protein that stabilizes the actin-based contractile ring during cytokinesis. To elucidate the underlying intermolecular interactions between actin filaments and anillin, we utilized total internal reflection fluorescence microscopy (TIRFM) and high-speed atomic force microscopy (Hs-AFM). Single-molecule imaging of anillin using TIRFM showed that anillin exists as monomers with relatively low binding affinity for actin filaments. Real-time imaging of actin filament cross-linking dynamics induced by anillin using Hs-AFM revealed that anillin monomers cross-link with actin filaments at a distance of 8 nm and that the polarity of those filaments is both parallel and antiparallel. These results are consistent with anillin playing a role in actin ring transition in vivo, where it might be responsible for thinning the ring-shaped apolar actin bundles.

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Actin dynamics and cofilin‐actin rods in alzheimer disease

2016

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Cytoskeletal abnormalities and synaptic loss, typical of both familial and sporadic Alzheimer disease (AD), are induced by diverse stresses such as neuroinflammation, oxidative stress, and energetic stress, each of which may be initiated or enhanced by proinflammatory cytokines or amyloid-β (Aβ) peptides. Extracellular Aβ-containing plaques and intracellular phospho-tau-containing neurofibrillary tangles are postmortem pathologies required to confirm AD and have been the focus of most studies. However, AD brain, but not normal brain, also have increased levels of cytoplasmic rod-shaped bundles of filaments composed of ADF/cofilin-actin in a 1:1 complex (rods). Cofilin, the major ADF/cofilin isoform in mammalian neurons, severs actin filaments at low cofilin/actin ratios and stabilizes filaments at high cofilin/actin ratios. It binds cooperatively to ADP-actin subunits in F-actin. Cofilin is activated by dephosphorylation and may be oxidized in stressed neurons to form disulfide-linked dimers, required for bundling cofilin-actin filaments into stable rods. Rods form within neurites causing synaptic dysfunction by sequestering cofilin, disrupting normal actin dynamics, blocking transport, and exacerbating mitochondrial membrane potential loss. Aβ and proinflammatory cytokines induce rods through a cellular prion protein-dependent activation of NADPH oxidase and production of reactive oxygen species. Here we review recent advances in our understanding of cofilin biochemistry, rod formation, and the development of cognitive deficits. We will then discuss rod formation as a molecular pathway for synapse loss that may be common between all three prominent current AD hypotheses, thus making rods an attractive therapeutic target.

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Cofilin-induced unidirectional cooperative conformational changes in actin filaments revealed by high-speed atomic force microscopy

Cited by 125 publications

References 72 publications

The actin filament twist changes abruptly at boundaries between bare and cofilin-decorated segments

The actin filament twist changes abruptly at boundaries between bare and cofilin-decorated segments

Visualizing dynamic actin cross‐linking processes driven by the actin‐binding protein anillin

Actin dynamics and cofilin‐actin rods in alzheimer disease

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