From the first to the second domain of gelsolin: a common path on the surface of actin?<sup>1</sup>

Irobi, Edward; Burtnick, Leslie D.; Urosev, Dunja; Narayan, K A; Robinson, Robert

doi:10.1016/s0014-5793(03)00934-7

Cited by 41 publications

(47 citation statements)

References 29 publications

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“…This study showed that the two stretches of amino acid sequences, the residues 148 -152 (GFKHV) in the g1-g2 linker and the residues 108 -114 (LDDYLNG) in the G1 domain, as well as the exact length of the g1-g2 linker are critical for the F-actin depolymerization function of the gelsolin (16,17). The structure of the F-actin depolymerization-competent 25-160-residue fragment of gelsolin in complex with the actin supported the hypothesis that the partial G2 domain binds along the side of the actin filament in such a way that it targets the G1 domain to intercalate between the actin subunit bound to G2 and the adjacent actin subunit and to rupture the noncovalent interactions holding them together (18). The opening of the G1 domain from rest of the molecule might thus be a prerequisite for the F-actin depolymerization function of gelsolin as has also been supported by the recent studies (3,4).…”

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confidence: 85%

Global Shapes of F-actin Depolymerization-competent Minimal Gelsolins

Peddada¹,

Sagar²,

Rathore³

et al. 2013

Journal of Biological Chemistry

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Background: Shape-function studies are necessary to design better therapeutic alternatives of the plasma gelsolin. Results: N-terminal fragment 30 -161 is the smallest segment with F-actin depolymerization potential, and G1-G3 can function independent of Ca 2ϩ ions or low pH. Conclusion: The g2-g3 linker plays a role in imparting pH/Ca 2ϩ insensitivity to G1-G3. Significance: We provide the first evidence that g2-g3 linker regulates mobility of the G1 domain.

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confidence: 85%

Global Shapes of F-actin Depolymerization-competent Minimal Gelsolins

Peddada¹,

Sagar²,

Rathore³

et al. 2013

Journal of Biological Chemistry

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“…The goal of this study was to better describe the structural basis of the interaction of villin with Ca 2ϩ to elucidate the molecular basis of cytoskeletal reorganization by villin. Of all the proteins of the villin superfamily, the Ca 2ϩ -binding sites are best described for the homologous protein gelsolin, which has been crystallized in the presence of actin and Ca 2ϩ ions (15)(16)(17)(18)(19). However, even for this protein, the Ca 2ϩ binding sites regulating actin capping and actin severing have not been functionally distinguished.…”

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confidence: 99%

Functional Dissection and Molecular Characterization of Calcium-sensitive Actin-capping and Actin-depolymerizing Sites in Villin

Kumar

Tomar

Parrill

et al. 2004

Journal of Biological Chemistry

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All proteins of the villin superfamily, which includes the actin-capping and -severing proteins such as gelsolin, scinderin, and severin, are calcium-regulated actinmodifying proteins. Like some of these proteins, villin has morphologically distinct effects on actin assembly depending on the free calcium concentrations. At physiological calcium (Ca 2؉ ) villin nucleates and bundles actin, whereas at higher concentrations it caps (>50 M) and severs (>200 M) actin filaments. Although Ca 2؉ -binding sites have been described in villin, the functional characterization of these sites has not been done previously. In the present study we functionally dissect the calcium-dependent actin-capping and -depolymerizing sites in villin. Our analysis reveals that villin binds Ca 2؉ with a K d of 80.5 M, a stoichiometry of 5.97, and a Hill's coefficient of 1.2. Using the NMR structure of villin 14T and the gelsolin-actin/Ca 2؉ crystal structure, six putative sites that result in Ca 2؉ -induced conformational changes were identified in human villin and confirmed by mutational analysis. Molecular dynamics studies support the mutational analysis and provide a model for structural difference in the A93G mutant that prevents the calcium-induced conformational changes in the S1 domain of villin. Furthermore, we determined that villin expresses at least two types of Ca 2؉ -sensitive sites that determine separate functional properties; site 1 (Glu-25, Asp-44, and Glu-74) regulates actin-capping, whereas sites 1 and 2 (Asp-86, Ala-93, and Asp-61), together with the intra-domain calcium-sensitive sites in villin, regulate actin depolymerization by villin. This is the first study that employs sequential mutagenesis to biochemically and functionally characterize the calcium-sensitive sites in villin. Such mutational analysis and functional characterization of the actin-capping and -depolymerizing sites are unknown for other proteins of the villin family.

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“…From sequence similarity, they inferred common ancestry. The enlarged WH2 domain is gaining currency [2][3][4], yet evidence for such a relationship is lacking.b-Thymosins are 43 residue peptides with a role in actin dynamics as monomer-sequestering agents [5]. Recently, a number of proteins containing internal tandem repeats of sequences very similar to monomeric b-thymosins have been identified, first in Drosophila and Caenorhabditis [6], more recently in Ciona, Dermacentor and Hermissenda [7].…”

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“…From sequence similarity, they inferred common ancestry. The enlarged WH2 domain is gaining currency [2][3][4], yet evidence for such a relationship is lacking.…”

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Are β‐thymosins WH2 domains?

Edwards

2004

FEBS Letters

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In their review ''WH2 domains: a small, versatile adapter for actin monomers '', Paunola et al. [1] drew attention to sequence similarity between members of two families of actin-binding sequences, WH2 domains and b-thymosins. The authors represented the two as a single family, by extending the original definition of WH2 domains from 18 to 35 residues. From sequence similarity, they inferred common ancestry. The enlarged WH2 domain is gaining currency [2][3][4], yet evidence for such a relationship is lacking.b-Thymosins are 43 residue peptides with a role in actin dynamics as monomer-sequestering agents [5]. Recently, a number of proteins containing internal tandem repeats of sequences very similar to monomeric b-thymosins have been identified, first in Drosophila and Caenorhabditis [6], more recently in Ciona, Dermacentor and Hermissenda [7]. From studies of the Drosophila protein ciboulot [8], the role of these proteins in regulation of actin filaments is likely to be different from monomeric thymosins. Homologues of b-thymosins have not been identified in single-celled organisms. WH2 domains [9] (from Wiskott-Aldrich homology 2) are 18-residue sequences that also confer actin binding, are known only as modular parts of larger proteins, but are widely distributed in phylogeny, being found in bacteria (hypothetical proteins in Rickettsia montana and Vibrio parahaemolyticus), certain viruses of arthropods, single-celled eukaryotes and metazoans, although not plants.Co-alignment of monomeric thymosins, thymosin repeats and WH2 domains [1] usefully highlighted similarity between the conserved C-terminus of WH2 domains and the hexapeptide motif LKKTET of thymosins, the latter residues long implicated in actin binding [10,11]. However, aligning thymosin repeats and WH2 domains separately (Fig. 1) shows that their patterns of conservation are not co-extensive: there is strong conservation of residues in thymosin repeats C-terminal of this motif, whereas conservation of WH2 domains is Nterminal from it. C-terminal sequences flanking the 18-mer WH2 domains are very heterogeneous, some reach C-terminus of the protein within the conserved span of thymosin repeats, and in others, adjacent WH2 domains overlap into this span.The similarity between these two families of actin binding modules is too low for their relatedness to be detected by similarity searches. For example, a Hidden Markov Model [15] constructed from the alignment of all 28 known tandem thymosin repeats, used to search non-redundant proteins, finds monomeric thymosins, but not WH2 domains. Conversely, an HMM based on the WH2 PFAM seed [16], with or without augmentation by 18 downstream residues, does not detect thymosins.The LKKTET motif, or variants, has been found in actinbinding proteins unrelated to thymosins or WH2 domains, such as vertebrate protein kinases C-e (LKKQET) [17] and so may have evolved independently in response to a shared mode of binding to actin. A suggested variant FKHVXPN in the link region of gelsolin is of particular interest, sin...

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From the first to the second domain of gelsolin: a common path on the surface of actin?¹

Cited by 41 publications

References 29 publications

Global Shapes of F-actin Depolymerization-competent Minimal Gelsolins

Global Shapes of F-actin Depolymerization-competent Minimal Gelsolins

Functional Dissection and Molecular Characterization of Calcium-sensitive Actin-capping and Actin-depolymerizing Sites in Villin

Are β‐thymosins WH2 domains?

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From the first to the second domain of gelsolin: a common path on the surface of actin?1

Cited by 41 publications

References 29 publications

Global Shapes of F-actin Depolymerization-competent Minimal Gelsolins

Global Shapes of F-actin Depolymerization-competent Minimal Gelsolins

Functional Dissection and Molecular Characterization of Calcium-sensitive Actin-capping and Actin-depolymerizing Sites in Villin

Are β‐thymosins WH2 domains?

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From the first to the second domain of gelsolin: a common path on the surface of actin?¹