Structural basis of actin filament nucleation and processive capping by a formin homology 2 domain

Otomo, Takanori; Tomchick, Diana R.; Panchal, Sanjay C.; Machius, Mischa; Rosen, Michael K.

doi:10.1038/nature03251

Cited by 336 publications

(587 citation statements)

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“…FH2 domains, comprised of dimers linked by flexible tethers, bind to and stabilize actin dimer intermediates. Formins processively elongate filaments by creating an environment at the barbed ( þ ) end that favors monomer addition (Otomo et al, 2005). The crystal structures (Xu et al, 2004;Otomo et al, 2005) of yeast and mammalian formins revealed unique 'lasso and post'-like dimers between FH2 domains.…”

Section: Q-myelodysplastic Syndromesmentioning

confidence: 99%

“…Formins processively elongate filaments by creating an environment at the barbed ( þ ) end that favors monomer addition (Otomo et al, 2005). The crystal structures (Xu et al, 2004;Otomo et al, 2005) of yeast and mammalian formins revealed unique 'lasso and post'-like dimers between FH2 domains. This so-called 'tethered dimer' allows for a dynamic association with the barbed end of growing filaments.…”

Section: Q-myelodysplastic Syndromesmentioning

confidence: 99%

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5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

et al. 2009

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Section: Q-myelodysplastic Syndromesmentioning

confidence: 99%

Section: Q-myelodysplastic Syndromesmentioning

confidence: 99%

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

et al. 2009

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“…Although the significance of this antiparallel actin dimer remains an open question, its structure does not relate to the native F-actin interfaces, in which protomers are arranged head-to-tail in parallel filaments. Finally, a recent structure of the protein formin in complex with two actin protomers has been used to provide some detail about the lateral or side-by-side interaction between two actin protomers in adjacent strands of the F-actin filament (29). Here, we report a crystal structure of a longitudinal actin dimer, which illuminates how actin protomers most likely touch each other along the vertical direction within the individual strands of the F-actin filament.…”

mentioning

confidence: 99%

The crystal structure of a cross-linked actin dimer suggests a detailed molecular interface in F-actin

Kudryashov

Sawaya

Adisetiyo

et al. 2005

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

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The 2.5-Å resolution crystal structure is reported for an actin dimer, composed of two protomers cross-linked along the longitudinal (or vertical) direction of the F-actin filament. The crystal structure provides an atomic resolution view of a molecular interface between actin protomers, which we argue represents a near-native interaction in the F-actin filament. The interaction involves subdomains 3 and 4 from distinct protomers. The atomic positions in the interface visualized differ by 5-10 Å from those suggested by previous models of F-actin. Such differences fall within the range of uncertainties allowed by the fiber diffraction and electron microscopy methods on which previous models have been based. In the crystal, the translational arrangement of protomers lacks the slow twist found in native filaments. A plausible model of F-actin can be constructed by reintroducing the known filament twist, without disturbing significantly the interface observed in the actin dimer crystal.actin crystal structure ͉ F-actin filament ͉ motor proteins A ctin is one of the most highly conserved proteins in nature, where it plays key roles in contraction, cell shape and motility, and subcellular organization. Actin's myriad functions are regulated by protein-protein interactions. Besides interacting with an enormously diverse set of other cellular proteins (1), actin's most critical functions arise from its interactions with itself as it assembles to form F-actin filaments. Because actin carries out its cellular functions through its filamentous form, knowing the detailed structure of actin filaments is an important step in achieving a mechanistic understanding of actin function.Our understanding of actin has been advanced greatly by intensive investigation into its three-dimensional (3D) structure. Because the filamentous form of actin is essentially incompatible with the growth of 3D crystals, crystallographic studies have focused on actin in its monomeric form. The 3D structure of monomeric actin (G-actin) was determined first by Kabsch et al.(2) as a complex, with DNase I serving as a polymerization inhibitor. The crystal structure of monomeric actin has since been determined at atomic resolution under a variety of conditions, varying, for example, in actin isoform (3), the identity of the bound nucleotide (4, 5), and in the identity of the other proteins (6, 7) or small molecules added as polymerization inhibitors (8, 9). As a consequence, the structure of the actin monomer (G-actin) is understood in considerable detail, although some important issues remain open regarding nucleotide-dependent changes in G-actin structure, including a possible transition between the open and closed nucleotide cleft conformations and the order-disorder shift of the DNase I-binding loop (4,7,10).Structural models of the actin filament have derived mainly from methods other than crystallography. The first structural model of F-actin was obtained by Holmes et al. (11), by using fiber-diffraction data extending to 8.4-Å resolution to determi...

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“…This activity occurs through the formin-homology (FH) 2 domain, which dimerizes to form a doughnut-shaped structure containing multiple actin-binding sites in its core Otomo et al, 2005b). This dimer is thought to stabilize otherwise unstable intermediates in the assembly of new actin filaments, and it binds processively to the fast-elongating barbed end of existing actin filaments (Pring et al, 2003;Kovar and Pollard, 2004).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the Formin for3p by cdc42p and bud6p

Martin

Rincón

Basu

et al. 2007

MBoC

138

167

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Formins are conserved actin nucleators responsible for the assembly of diverse actin structures. Many formins are controlled through an autoinhibitory mechanism involving the interaction of a C-terminal DAD sequence with an N-terminal DID sequence. Here, we show that the fission yeast formin for3p, which mediates actin cable assembly and polarized cell growth, is regulated by a similar autoinhibitory mechanism in vivo. Multiple sites govern for3p localization to cell tips. The localization and activity of for3p are inhibited by an intramolecular interaction of divergent DAD and DID-like sequences. A for3p DAD mutant expressed at endogenous levels produces more robust actin cables, which appear to have normal organization and dynamics. We identify cdc42p as the primary Rho GTPase involved in actin cable assembly and for3p regulation. Both cdc42p, which binds at the N terminus of for3p, and bud6p, which binds near the C-terminal DAD-like sequence, are needed for for3p localization and full activity, but a mutation in the for3p DAD restores for3p localization and other phenotypes of cdc42 and bud6 mutants. In particular, the for3p DAD mutation suppresses the bipolar growth (NETO) defect of bud6⌬ cells. These findings suggest that cdc42p and bud6p activate for3p by relieving autoinhibition. INTRODUCTIONFormins are key regulators of the actin cytoskeleton and form a large family conserved in all eukaryotes Faix and Grosse, 2006). These proteins are necessary for the formation of numerous actin structures, including stress fibers, filopodia, cytokinetic actin rings, junctional actin structures, or actin cables. The proper regulation of formins is likely to be critical for cellular processes such as cell migration, cytokinesis, cell adhesion, and cell polarity.A well characterized biochemical activity of formins is to nucleate and elongate linear actin filaments Sagot et al., 2002b;Kovar et al., 2003;Li and Higgs, 2003;Moseley et al., 2004). This activity occurs through the formin-homology (FH) 2 domain, which dimerizes to form a doughnut-shaped structure containing multiple actin-binding sites in its core Otomo et al., 2005b). This dimer is thought to stabilize otherwise unstable intermediates in the assembly of new actin filaments, and it binds processively to the fast-elongating barbed end of existing actin filaments (Pring et al., 2003;Kovar and Pollard, 2004).The adjacent FH1 domain binds profilin-actin and helps accelerate the elongation of actin filaments (Chang et al., 1997;Evangelista et al., 1997;Watanabe et al., 1997;Romero et al., 2004;Kovar et al., 2006). The budding yeast formin Bni1p also binds the actin monomer-binding protein Bud6p, which, similar to profilin, stimulates the activity of the FH2 domain (Moseley and Goode, 2005). In addition to their activity in actin filament nucleation and elongation, some formins have been suggested to also function in actin bundling and severing, further contributing to the remodeling of actin structures (Harris et al., 2004Moseley and Goode, 2005;Harris et al., 2006...

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Structural basis of actin filament nucleation and processive capping by a formin homology 2 domain

Cited by 336 publications

References 33 publications

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

The crystal structure of a cross-linked actin dimer suggests a detailed molecular interface in F-actin

Regulation of the Formin for3p by cdc42p and bud6p

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