Actin-bundling protein

  • 文章类型: Journal Article
    Adjuvant chemotherapy has been carried out for patients with cancer who underwent curative resection, but it is basically not needed for patients without micro-metastatic lesions who undergo a perfectly curative surgical operation. The patients who need adjuvant chemotherapy are defined as those whose micro-metastases cannot be detected by imaging modalities in the other sites of the resective areas, despite curative resection for the primary sites. If biomarkers to efficiently evaluate the metastatic potential of each patient could be developed, we may be able to provide personalized adjuvant chemotherapy in the clinical setting. Actinin-4 (ACTN4, gene name ACTN4) is an actin-bundling protein that we identified in 1998 as a novel molecule involved in cancer invasion and metastasis. Protein overexpression of actinin-4 in cancer cells leads to the invasive phenotype, and patients with gene amplification of ACTN4 have a worse prognosis than patients with a normal copy number in some cancers, including pancreas, lung, and salivary gland cancers. In this review, the biological roles of actinin-4 for cancer invasion and metastasis are summarized, and the potential usefulness of actinin-4 as a biomarker for evaluation of metastatic ability is examined.
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  • 文章类型: Journal Article
    Fascin,一种肌动蛋白捆绑蛋白,在肌动蛋白丝(F-actin)的交联中起着重要作用。Fascin的磷酸化是影响其结构和功能的重要翻译后修饰。例如,Fascin-S39D的磷模拟突变显着降低了其与F-肌动蛋白的捆绑能力。在本文中,我们通过分子动力学(MD)模拟和生化方法研究了Fascin的肌动蛋白捆绑活性。通过MD模拟模拟模拟从丝氨酸/苏氨酸到天冬氨酸的所有单位点突变。对于五个突变体(S146D,S156D,S218D,T239D和S259D),发现Fascin结构域2中的突变残基与相邻残基形成盐桥相互作用,表明这些残基的突变可能会降低肌动蛋白捆绑活性。Further,F-肌动蛋白捆绑测定和免疫荧光技术显示S146D和T239D对Fascin与F-肌动蛋白捆绑具有强烈影响。最后,我们表明,单位点突变不会改变Fascin的一般形状,但是Fascin-S146D和T239D中突变残基附近的局部结构变得不稳定,从而影响Fascin与F-肌动蛋白结合的能力。这些发现表明Fascin的靶向结构域2对于药物设计将是非常有用的。此外,我们的研究表明,MD模拟是筛选Fascin上重要残基的有用方法。
    Fascin, one of actin bundling proteins, plays an important role in the cross-linking of actin filaments (F-actin). Phosphorylation of Fascin is an important posttranslational modification to affect its structure and function. For example, a phosphomimetic mutation of Fascin-S39D decrease its bundling ability with F-actin significantly. In this paper, we studied the actin-bundling activity of Fascin by using molecular dynamics (MD) simulations and biochemical methods. All single-site mutations from serine/threonine to aspartic acid were mimicked by MD simulations. For five mutants (S146D, S156D, S218D, T239D and S259D), the mutated residues in domain 2 of Fascin were found to form salt-bridge interactions with an adjacent residue, indicating that mutations of these residues could potentially reduce actin-bundling activity. Further, F-actin-bundling assays and immunofluorescence technique showed S146D and T239D to have a strong effect on Fascin bundling with F-actin. Finally, we show that single-site mutations do not change the general shape of Fascin, but local structures near the mutated residues in Fascin-S146D and T239D become unstable, thereby affecting the ability of Fascin to bind with F-actin. These findings suggest that targeting domain 2 of Fascin would be very useful for the drug design. In addition, our study indicates that MD simulation is a useful method to screening which residues on Fascin are important.
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  • 文章类型: Journal Article
    Ca2+ regulates several cellular functions, including signaling events, energy production, and cell survival. These cellular processes are mediated by Ca2+-binding proteins, such as EF-hand superfamily proteins. Among the EF-hand superfamily proteins, allograft inflammatory factor-1 (AIF-1) and swiprosin-1/EF-hand domain-containing protein 2 (EFhd2) are cytosolic actin-binding proteins. AIF-1 modulates the cytoskeleton and increases the migration of immune cells. EFhd2 is also a cytoskeletal protein implicated in immune cell activation and brain cell functions. EFhd1, a mitochondrial fraternal twin of EFhd2, mediates neuronal and pro-/pre-B cell differentiation and mitoflash activation. Although EFhd1 is important for maintaining mitochondrial morphology and energy synthesis, its mechanism of action remains unclear. Here, we report the crystal structure of the EFhd1 core domain comprising a C-terminus of a proline-rich region, two EF-hand domains, and a ligand mimic helix. Structural comparisons of EFhd1, EFhd2, and AIF-1 revealed similarities in their overall structures. In the structure of the EFhd1 core domain, two Zn2+ ions were observed at the interface of the crystal contact, suggesting the possibility of Zn2+-mediated multimerization. In addition, we found that EFhd1 has Ca2+-independent β-actin-binding and Ca2+-dependent β-actin-bundling activities. These findings suggest that EFhd1, an actin-binding and -bundling protein in the mitochondria, may contribute to the Ca2+-dependent regulation of mitochondrial morphology and energy synthesis.
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  • 文章类型: Journal Article
    Neuromuscular junctions (NMJs) govern efficient neuronal communication with muscle cells, relying on proper architecture of specialized postsynaptic compartments. However, the intrinsic mechanism in muscle cells contributing to NMJ development remains unclear. In this study, we reveal that dynamin-2 (Dyn2) is involved in postsynaptic development of NMJs. Mutations of Dyn2 have been linked to human muscular disorder and centronuclear myopathy (CNM), as well as featured with muscle atrophy and defective NMJs, yet the function of Dyn2 at the postsynaptic membrane is largely unknown. We demonstrate that Dyn2 is enriched at the postsynaptic membrane and regulates NMJ development via actin remodeling. Dyn2 functions as an actin-bundling GTPase to regulate podosome turnover and cytoskeletal organization of the postsynaptic apparatus, and CNM-Dyn2 mutations display abnormal actin remodeling and electrophysiological activity of fly NMJs. Altogether, Dyn2 primarily regulates actin cytoskeleton remodeling and NMJ morphogenesis at the postsynaptic membrane, which is distinct from its endocytosis regulatory role at the presynaptic membrane.
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  • 文章类型: Journal Article
    A contractile ring (CR) is involved in cytokinesis in animal and yeast cells. Although several types of actin-bundling proteins associate with F-actin in the CR, their individual roles in the CR have not yet been elucidated in detail. Ain1 is the sole α-actinin homologue in the fission yeast Schizosaccharomyces pombe and specifically localizes to the CR with a high turnover rate. S. pombe cells lacking the ain1+ gene show defects in cytokinesis under stress conditions. We herein investigated the biochemical activity and cellular localization mechanisms of Ain1. Ain1 showed weaker affinity to F-actin in vitro than other actin-bundling proteins in S. pombe. We identified a mutation that presumably loosened the interaction between two calponin-homology domains constituting the single actin-binding domain (ABD) of Ain1, which strengthened the actin-binding activity of Ain1. This mutant protein induced a deformation in the ring shape of the CR. Neither a truncated protein consisting only of an N-terminal ABD nor a truncated protein lacking a C-terminal region containing an EF-hand motif localized to the CR, whereas the latter was involved in the bundling of F-actin in vitro. We herein propose detailed mechanisms for how each part of the molecule is involved in the proper cellular localization and function of Ain1.
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  • 文章类型: Journal Article
    Invasion and metastasis are malignant phenotypes in cancer that lead to patient death. Cell motility is involved in these processes. In 1998, we identified overexpression of the actin-bundling protein actinin-4 in several types of cancer. Protein expression of actinin-4 is closely associated with the invasive phenotypes of cancers. Actinin-4 is predominantly expressed in the cellular protrusions that stimulate the invasive phenotype in cancer cells and is essential for formation of cellular protrusions such as filopodia and lamellipodia. ACTN4 (gene name encoding actinin-4 protein) is located on human chromosome 19q. ACTN4 amplification is frequently observed in patients with carcinomas of the pancreas, ovary, lung, and salivary gland, and patients with ACTN4 amplifications have worse outcomes than patients without amplification. In addition, nuclear distribution of actinin-4 is frequently observed in small cell lung, breast, and ovarian cancer. Actinin-4, when expressed in cancer cell nuclei, functions as a transcriptional co-activator. In this review, we summarize recent developments regarding the biological roles of actinin-4 in cancer invasion.
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