How depolymerization can promote polymerization: the case of actin and profilin

Yarmola, Elena G.; Bubb, Michael R.

doi:10.1002/bies.200900049

Cited by 44 publications

(37 citation statements)

References 83 publications

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“…After it is bound, the actin-actin interactions would induce the G-to F-actin structural transition in the newly incorporated protomer away from the optimal conformations that favor binding of profilin or WH2s, leading to the release of bound profilin or WH2 and an uncapped barbed end ready for the incorporation of the next actin protomer. Indeed, there have been continued efforts in the literature aimed at elucidating the interplay between profilin, G-actin, and the barbed end of F-actin (44,(48)(49)(50)(51)(52). A recent report detailing kinetic rates at the single-filament level (53) strongly suggests that the conformations of protomers at the barbed end of F-actin differ from those of G-actin.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of thymosin-β4/profilin exchange leading to actin filament polymerization

Xue

Leyrat

Grimes

et al. 2014

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

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Thymosin-β4 (Tβ4) and profilin are the two major sequestering proteins that maintain the pool of monomeric actin (G-actin) within cells of higher eukaryotes. Tβ4 prevents G-actin from joining a filament, whereas profilin:actin only supports barbed-end elongation. Here, we report two Tβ4:actin structures. The first structure shows that Tβ4 has two helices that bind at the barbed and pointed faces of G-actin, preventing the incorporation of the bound G-actin into a filament. The second structure displays a more open nucleotide binding cleft on G-actin, which is typical of profilin:actin structures, with a concomitant disruption of the Tβ4 C-terminal helix interaction. These structures, combined with biochemical assays and molecular dynamics simulations, show that the exchange of bound actin between Tβ4 and profilin involves both steric and allosteric components. The sensitivity of profilin to the conformational state of actin indicates a similar allosteric mechanism for the dissociation of profilin during filament elongation.is maintained at levels far above the critical concentration for polymerization (0.1 μM) (1) in specific areas of a mammalian cell. In lamellipodia, the levels of G-actin and filamentous actin (F-actin) are estimated to be 150 and 500 μM, respectively (2). Generally, actin filaments are thought to be capped to prevent nonproductive polymerization, whereas actively elongating filaments are created through controlled uncapping, severing, or de novo nucleation mechanisms (3) to harness the force of polymerization for a particular biological process. The availability of the pool of G-actin is tightly regulated through the binding of two classes of G-actin sequestering proteins (3, 4). β-Thymosins are short peptides (∼43 aa) that are able to completely sequester G-actin, preventing G-actin from forming a nucleus or joining either end of an existing actin filament. Profilins (molecular mass ∼ 16 kDa), in isolation, also sequester G-actin, precluding nucleation or participation in pointed-end filament elongation. In contrast, they actively participate in barbed-end filament elongation, dissociating from the actin protomer as it is incorporated into the filament. In the presence of actin nucleation and elongation machineries, such as actin-related protein 2/3 complex activators, formins, Wiskott-Aldrich syndrome protein (WASP) homology domain 2 (WH2)-containing nucleators [Spire, protein Cordon-bleu (Cobl), and VopF/L], and vasodilator-stimulated phosphoprotein (VASP) (5, 6), profilin plays an active role in the nucleation and elongation processes.Cellular concentrations of thymosin-β4 (Tβ4) are in the 100-to 500-μM range, and its association with ATP-and ADP-bound actin is characterized by dissociation constant (K d ) values of 0.1-3.9 and 80-100 μM, respectively (7-11). Profilin I has been reported to be at a concentration of 8.4 μM in CHO cells (12) and can amount from 14% to 100% of the G-actin pool in other cells (13). Profilin I interacts with actin with K d values of 0.1 and 0.17 μM for ATP-an...

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Section: Discussionmentioning

confidence: 99%

Structural basis of thymosin-β4/profilin exchange leading to actin filament polymerization

Xue

Leyrat

Grimes

et al. 2014

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

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“…Paradoxically, this faster rate of deplomerization can promote net polymerization by accelerating ATP-replacement of actin monomers. [73][74][75][76] Even though there is a mechanistic difference between the two models, both build upon the fundamental idea of Pfn1 utilizing its actin and PLP interactions to promote net actin polymerization at the leading edge and in turn, driving membrane protrusion during cell migration.…”

Section: Actin-dependent Function Of Pfn1 In Cell Motilitymentioning

confidence: 99%

Molecular insights on context-specific role of profilin-1 in cell migration

Ding

Bae

Roy

2012

Cell Adhesion & Migration

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“…In the presence of formin, profilin promotes the elongation of the uncapped barbed end of the actin filament. When the barbed ends are capped, profilin promotes the disassembly of the actin filament 14 . Although profilin-1 and profilin-2 have similar properties, only profilin-1 is an essential molecule that shows dose-dependent effects on cell division and survival during embryogenesis in mice.…”

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confidence: 99%

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

et al. 2015

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Altered transforming growth factor-b (TGF-b) signalling has been implicated in tumour development and progression. However, the molecular mechanism behind this alteration is poorly understood. Here we show that profilin-2 (Pfn2) increases Smad2 and Smad3 expression via an epigenetic mechanism, and that profilin-2 and Smad expression correlate with an unfavourable prognosis of lung cancer patients. Profilin-2 overexpression promotes, whereas profilin-2 knockdown drastically reduces, lung cancer growth and metastasis. We show that profilin-2 suppresses the recruitment of HDAC1 to Smad2 and Smad3 promoters by preventing nuclear translocation of HDAC1 through protein-protein interaction at the C terminus of both proteins, leading to the transcriptional activation of Smad2 and Smad3. Increased Smad2 and Smad3 expression enhances TGF-b1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-b1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.

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How depolymerization can promote polymerization: the case of actin and profilin

Cited by 44 publications

References 83 publications

Structural basis of thymosin-β4/profilin exchange leading to actin filament polymerization

Structural basis of thymosin-β4/profilin exchange leading to actin filament polymerization

Molecular insights on context-specific role of profilin-1 in cell migration

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

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