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Actin Capping

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Alla S Kostyukova – One of the best experts on this subject based on the ideXlab platform.

  • alteration of tropomyosin binding properties of tropomodulin 1 affects its Capping ability and localization in skeletal myocytes
    Journal of Biological Chemistry, 2013
    Co-Authors: Natalia Moroz, Alla S Kostyukova, Stefanie M. Novak, Carol C Gregorio, Ricardo Azevedo, Mert Colpan, Vladimir N Uversky
    Abstract:

    Tropomodulin (Tmod) is an ActinCapping protein that binds to the two tropomyosins (TM) at the pointed end of the Actin filament to prevent further Actin polymerization and depolymerization. Therefore, understanding the role of Tmod is very important when studying Actin filament dependent processes such as muscle contraction and intracellular transport. The Capping ability of Tmod is highly influenced by TM and is 1000-fold greater in the presence of TM. There are four Tmod isoforms (Tmod1–4), three of which, Tmod1, Tmod3, and Tmod4, are expressed in skeletal muscles. The affinity of Tmod1 to skeletal striated TM (stTM) is higher than that of Tmod3 and Tmod4 to stTM. In this study, we tested mutations in the TM-binding sites of Tmod1, using circular dichdichroism (CD) and prediction analysis (PONDR). The mutations R11K, D12N, and Q144K were chosen because they decreased the affinity of Tmod1 to stTM, making it similar to that of affinity of Tmod3 and Tmod4 to stTM. Significant reduction of inhibition of Actin pointed-end polymerization in the presence of stTM was shown for Tmod1 (R11K/D12N/Q144K) as compared with WT Tmod1. When GFP-Tmod1 and mutants were expressed in primary chicken skeletal myocytes, decreased assembly of Tmod1 mutants was revealed. This indicates a direct correlation between TM-binding and the ActinCapping abilities of Tmod. Our data confirmed the hypothesis that assembly of Tmod at the pointed-end of the Actin filament depends on its TM-binding affinity.

  • alteration of tropomyosin binding properties of tropomodulin 1 affects its Capping ability and localization
    , 2013
    Co-Authors: Natalia Moroz, Stefanie M. Novak, Carol C Gregorio, Ricardo Azevedo, Mert Colpan, Vladimir N Uversky, Alla S Kostyukova
    Abstract:

    Tropomodulin (Tmod) is an ActinCapping protein that binds to the two tropomyosins (TM) at the pointed end of the Actin filament to prevent further Actin polymerization and depolymerization. Therefore, understanding the role of Tmod is very important when studying Actin filament dependent processes such as muscle contraction and intracellular transport. The Capping ability of Tmod is highly influenced by TM and is 1000-fold greater in the presence of TM. There are four Tmod isoforms (Tmod1– 4), three of which, Tmod1, Tmod3, and Tmod4, are expressed in skeletal muscles. The affinity of Tmod1 to skeletal striated TM (stTM) is higher than that of Tmod3 and Tmod4 to stTM. In this study, we tested mutations in the TM-binding sites of Tmod1, using circular dichdichroism (CD) and prediction analysis (PONDR). The mutations R11K, D12N, and Q144K were chosen because they decreased the affinity of Tmod1 to stTM, making it similar to that of affinity of Tmod3 and Tmod4 to stTM. Significant reduction of inhibition of Actin pointedend polymerization in the presence of stTM was shown for Tmod1 (R11K/D12N/Q144K) as compared with WT Tmod1. When GFP-Tmod1 and mutants were expressed in primary chicken skeletal myocytes, decreased assembly of Tmod1 mutants was revealed. This indicates a direct correlation between TM-binding and the ActinCapping abilities of Tmod. Our data confirmed the hypothesis that assembly of Tmod at the pointed-end of the Actin filament depends on

  • Identification of Residues within Tropomodulin-1 Responsible for Its Localization at the Pointed Ends of the Actin Filaments in Cardiac Myocytes
    Journal of Biological Chemistry, 2010
    Co-Authors: Takehiro Tsukada, Lucy Kotlyanskaya, Robert Huynh, Brinda Desai, Stefanie M. Novak, Andrey V. Kajava, Carol C Gregorio, Alla S Kostyukova
    Abstract:

    Tropomodulin is a tropomyosin-dependent Actin filament Capping protein involved in the structural formation of thin filaments and in the regulation of their lengths through its localization at the pointed ends of Actin filaments. The disordered N-terminal domain of tropomodulin contains three functional sites: two tropomyosin-binding and one tropomyosin-dependent ActinCapping sites. The C-terminal half of tropomodulin consists of one compact domain containing a tropomyosin-independent ActinCapping site. Here we determined the structural properties of tropomodulin-1 that affect its roles in cardiomyocytes. To explore the significance of individual tropomyosin-binding sites, GFP-tropomodulin-1 with single mutations that destroy each tropomyosin-binding site was expressed in cardiomyocytes. We demonstrated that both sites are necessary for the optimal localization of tropomodulin-1 at thin filafilament pointed ends, with site 2 Acting as the major determinant. To investigate the functional properties of the tropomodulin C-terminal domain, truncated versions of GFP-tropomodulin-1 were expressed in cardiomyocytes. We discovered that the leucine-rich repeat (LRR) fold and the C-terminal helix are required for its proper targeting to the pointed ends. To investigate the structural significance of the LRR fold, we generated three mutations within the C-terminal domain (V232D, F263D, and L313D). Our results show that these mutations affect both tropomyosin-independent ActinCapping activity and pointed end localization, most likely by changing local conformations of either loops or side chains of the surfaces involved in the interactions of the LRR domain. Studying the influence of these mutations individually, we concluded that, in addition to the tropomyosin-independent ActinCapping site, there appears to be another regulatory site within the tropomodulin C-terminal domain.

Marc Ladanyi – One of the best experts on this subject based on the ideXlab platform.

  • expression of f Actin Capping protein subunit beta capzb is associated with cell growth and motility in epithelioid sarcoma
    BMC Cancer, 2016
    Co-Authors: Kenta Mukaihara, Yoshiyuki Suehara, Shinji Kohsaka, Daisuke Kubota, Midori Todaishii, Keisuke Akaike, Tsutomu Fujimura, Eisuke Kobayashi, Takashi Yao, Marc Ladanyi
    Abstract:

    Background A previous proteomics study demonstrated the overexpression of F-Actin Capping protein subunit beta (CAPZB) in tissue specimens of epithelioid sarcoma (EpiS). The aim of the present study was to elucidate the function of CAPZB in EpiS.

  • Expression of F-ActinCapping protein subunit beta, CAPZB, is associated with cell growth and motility in epithelioid sarcoma
    BMC Cancer, 2016
    Co-Authors: Kenta Mukaihara, Yoshiyuki Suehara, Shinji Kohsaka, Daisuke Kubota, Keisuke Akaike, Tsutomu Fujimura, Eisuke Kobayashi, Takashi Yao, Midori Toda-ishii, Marc Ladanyi
    Abstract:

    Background A previous proteomics study demonstrated the overexpression of F-Actin Capping protein subunit beta (CAPZB) in tissue specimens of epithelioid sarcoma (EpiS). The aim of the present study was to elucidate the function of CAPZB in EpiS. Methods Cellular functional assays were performed in two EpiS cell lines using CAPZB siRNAs. In addition, comparative protein expression analyses using Isobaric Tags for Relative and Absolute Quantitation (i-TRAQ) method were performed to identify the specific proteins whose expression was dysregulated by CAPZB, and analysed the data with the Ingenuity Pathways Analysis (IPA) system using the obtained protein profiles to clarify the functional pathway networks associated with the oncogenic function of CAPZB in EpiS. Additionally, we performed functional assays of the INI1 protein using INI1-overexpressing EpiS cells. Results All 15 EpiS cases showed an immunohistochemical expression of CAPZB, and two EpiS cell lines exhibited a strong CAPZB expression. Silencing of CAPZB inhibited the growth, invasion and migration of the EpiS cells. Analysis of protein profiles using the IPA system suggested that SWI/SNF chromatin-remodeling complexes including INI1 may function as a possible upstream regulator of CAPZB. Furthermore, silencing of CAPZB resulted in a decreased expression of INI1 proteins in the INI1-positive EpiS cells, whereas the induction of INI1 in the INI1-deficient EpiS cells resulted in an increased CAPZB mRNA expression. Conclusions CAPZB is involved in tumor progression in cases of EpiS, irrespective of the INI1 expression, and may be a potential therapeutic target. The paradoxical relationship between the tumor suppressor INI1 and the oncoprotein CAPZB in the pathogenesis of EpiS remains to be clarified.

Jeffrey S. Simske – One of the best experts on this subject based on the ideXlab platform.

John A. Cooper – One of the best experts on this subject based on the ideXlab platform.

Sofia Khaitlina – One of the best experts on this subject based on the ideXlab platform.