Chivosazole A Modulates Protein-Protein Interactions of Actin.

Actin is a protein of central importance for many cellular key processes. It is regulated by local interactions with a large number of actin binding proteins (ABPs). Various compounds are known to either increase or decrease the polymerization dynamics of actin. However, no actin binding compound has been developed for clinical applications yet because of selectivity issues. We provide a crystal structure of the natural product chivosazole A (ChivoA) bound to actin and show that-in addition to inhibiting nucleation, polymerization, and severing of F-actin filaments-it selectively modulates binding of ABPs to G-actin: Although unphysiological actin dimers are induced by ChivoA, interaction with gelsolin, profilin, cofilin, and thymosin-β4 is inhibited. Moreover, ChivoA causes transcriptional effects differing from latrunculin B, an actin binder with a different binding site. Our data show that ChivoA and related compounds could serve as scaffolds for the development of actin binding molecules selectively targeting specific actin functions.

[1]  Emily Lin,et al.  Nuclear F-actin and myosins drive relocalization of heterochromatic breaks , 2018, Nature.

[2]  B. Chait,et al.  Nuclear Arp2/3 drives DNA break clustering for homology-directed repair , 2018, Nature.

[3]  Ying Lin,et al.  Functions of nuclear actin-binding proteins in human cancer. , 2017, Oncology letters.

[4]  Paul V. Ruijgrok,et al.  Author response: Cryo-EM structures reveal specialization at the myosin VI-actin interface and a mechanism of force sensitivity , 2017 .

[5]  M. Schirle,et al.  Direct Interaction of Chivosazole F with Actin Elicits Cell Responses Similar to Latrunculin A but Distinct from Chondramide. , 2017, ACS chemical biology.

[6]  Christoph Ziegenhain,et al.  zUMIs - A fast and flexible pipeline to process RNA sequencing data with UMIs , 2017, bioRxiv.

[7]  P. Heneberg,et al.  Migrastatics—Anti-metastatic and Anti-invasion Drugs: Promises and Challenges , 2017, Trends in cancer.

[8]  S. Kan,et al.  An Expedient Total Synthesis of Chivosazole F: an Actin‐Binding Antimitotic Macrolide from the Myxobacterium Sorangium Cellulosum , 2016, Angewandte Chemie.

[9]  W. Wood,et al.  Unravelling the Actin Cytoskeleton: A New Competitive Edge? , 2016, Trends in cell biology.

[10]  N. Parinandi,et al.  ACD toxin–produced actin oligomers poison formin-controlled actin polymerization , 2015, Science.

[11]  J. H. Pereira,et al.  Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues , 2014, ChemMedChem.

[12]  K. Diederichs,et al.  Better models by discarding data? , 2013, Acta crystallographica. Section D, Biological crystallography.

[13]  J. Gurdon,et al.  Transcriptional regulation and nuclear reprogramming: roles of nuclear actin and actin-binding proteins , 2012, Cellular and Molecular Life Sciences.

[14]  Jia-huai Wang.  Faculty Opinions recommendation of Biochemistry. Resolving some old problems in protein crystallography. , 2012 .

[15]  P. Evans.  Resolving Some Old Problems in Protein Crystallography , 2012, Science.

[16]  P. Andrew Karplus,et al.  Linking Crystallographic Model and Data Quality , 2012, Science.

[17]  P. Zwart,et al.  Towards automated crystallographic structure refinement with phenix.refine , 2012, Acta crystallographica. Section D, Biological crystallography.

[18]  Paul D. Adams,et al.  Use of knowledge-based restraints in phenix.refine to improve macromolecular refinement at low resolution , 2012, Acta crystallographica. Section D, Biological crystallography.

[19]  G. Schröder,et al.  Remodeling of actin filaments by ADF/cofilin proteins , 2011, Proceedings of the National Academy of Sciences.

[20]  Roman A. Laskowski,et al.  LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery , 2011, J. Chem. Inf. Model..

[21]  K. Holmes,et al.  Actin structure and function. , 2011, Annual review of biophysics.

[22]  M. Kalesse,et al.  Total synthesis of chivosazole F. , 2010, Journal of the American Chemical Society.

[23]  J. Kubanek,et al.  Two molecules of lobophorolide cooperate to stabilize an actin dimer using both their "ring" and "tail" region. , 2010, Chemistry & biology.

[24]  H. Reichenbach,et al.  Chivosazoles A and F, Cytostatic Macrolides from Myxobacteria, Interfere with Actin , 2009, Chembiochem : a European journal of chemical biology.

[25]  Gregor Hagelueken,et al.  The absolute configuration of rhizopodin and its inhibition of actin polymerization by dimerization. , 2009, Angewandte Chemie.

[26]  T. Yeates,et al.  Multiple crystal structures of actin dimers and their implications for interactions in the actin filament , 2008, Acta crystallographica. Section D, Biological crystallography.

[27]  K. Henrick,et al.  Inference of macromolecular assemblies from crystalline state. , 2007, Journal of molecular biology.

[28]  I. Rayment,et al.  A structural basis for regulation of actin polymerization by pectenotoxins. , 2007, Journal of molecular biology.

[29]  Randy J. Read,et al.  Phaser crystallographic software , 2007, Journal of applied crystallography.

[30]  M. Kalesse,et al.  Chivosazole A--elucidation of the absolute and relative configuration. , 2007, Angewandte Chemie.

[31]  I. Rayment,et al.  Actin-targeting natural products: structures, properties and mechanisms of action , 2006, Cellular and Molecular Life Sciences CMLS.

[32]  Kunio Hirata,et al.  Structure basis for antitumor effect of aplyronine a. , 2006, Journal of molecular biology.

[33]  Ivan Rayment,et al.  Structures of microfilament destabilizing toxins bound to actin provide insight into toxin design and activity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Ivan Rayment,et al.  Structural basis of swinholide A binding to actin. , 2005, Chemistry & biology.

[35]  Roberto Dominguez,et al.  Actin-binding proteins--a unifying hypothesis. , 2004, Trends in biochemical sciences.

[36]  L. Blanchoin,et al.  Structural basis of actin sequestration by thymosin‐β4: implications for WH2 proteins , 2004, The EMBO journal.

[37]  Ivan Rayment,et al.  Absolute stereochemistry of ulapualide A. , 2004, Organic letters.

[38]  I. Rayment,et al.  Biomolecular mimicry in the actin cytoskeleton: Mechanisms underlying the cytotoxicity of kabiramide C and related macrolides , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Ivan Rayment,et al.  Trisoxazole macrolide toxins mimic the binding of actin-capping proteins to actin , 2003, Nature Structural Biology.

[40]  R. Fletterick,et al.  Structure of an F-actin Trimer Disrupted by Gelsolin and Implications for the Mechanism of Severing* 210 , 2003, The Journal of Biological Chemistry.

[41]  Robert C Robinson,et al.  The calcium activation of gelsolin: insights from the 3A structure of the G4-G6/actin complex. , 2002, Journal of molecular biology.

[42]  D. Ringe,et al.  Reaction of alanine racemase with 1-aminoethylphosphonic acid forms a stable external aldimine , 1998, Biochemistry.

[43]  J. Lepault,et al.  T Is Not a Simple G-actin Sequestering Protein and Interacts with F-actin at High Concentration (*) , 1996, The Journal of Biological Chemistry.

[44]  H. Reichenbach,et al.  Chivosazol A, a new inhibitor of eukaryotic organisms isolated from myxobacteria. , 1995, The Journal of antibiotics.

[45]  C. Schutt,et al.  The structure of crystalline profilin–β-actin , 1993, Nature.

[46]  H. Reichenbach,et al.  Rhizopodin, a new compound from Myxococcus stipitatus (myxobacteria) causes formation of rhizopodia-like structures in animal cell cultures. Production, isolation, physico-chemical and biological properties. , 1993, The Journal of antibiotics.

[47]  K. Katagiri,et al.  ANTITUMOR ACTIVITY OF GYTOGHALASIN D , 1971 .

[48]  Firas Khatib,et al.  High-resolution structure of a retroviral protease folded as a monomer , 2011 .

[49]  Ram Seshadri.  Crystal structures , 2004 .

[50]  P. Afonine,et al.  research papers Acta Crystallographica Section D Biological , 2003 .

[51]  C. Schutt,et al.  The structure of crystalline profilin-beta-actin. , 1993, Nature.

[52]  K. Katagiri,et al.  Antitumor activity of cytochalasin D. , 1971, The Journal of antibiotics.