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Synaptopodin family of natively unfolded, actin binding proteins: physical properties and potential biological functions

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Abstract

The synaptopodin family of proteins consists of at least 3 members: synaptopodin, the synaptopodin 2 proteins, and the synaptopodin 2-like proteins. Each family member has at least 3 isoforms that are produced by alternative splicing. Synaptopodin family members are basic proteins that are rich in proline and have little regular 2° or 3° structure at physiological temperature, pH and ionic strength. Like other natively unfolded proteins, synaptopodin family members have multiple binding partners including actin and other actin-binding proteins. Several members of the synaptopodin family have been shown to stimulate actin polymerization and to bundle actin filaments either on their own or in collaboration with other proteins. Synaptopodin 2 has been shown to accelerate nucleation of actin filament formation and to induce actin bundling. The actin polymerization activity is inhibited by Ca2+-calmodulin. Synaptopodin 2 proteins are localized in Z-bands of striated and heart muscle and dense bodies of smooth muscle cells. Depending on the developmental status and stress, at least one member of the synaptopodin family can occupy nuclei of some cells. Members of the synaptopodin 2 subfamily have been implicated in cancers.

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References

  • Albiges-Rizo C, Destaing O, Fourcade B, Planus E, Block MR (2009) Actin machinery and mechanosensitivity in invadopodia, podosomes and focal adhesions. J Cell Sci 122:3037–3049

    Article  CAS  PubMed  Google Scholar 

  • Asanuma K, Kim K, Oh J, Giardino L, Chabanis S, Faul C, Reiser J, Mundel P (2005) Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner. J Clin Invest 115:1188–1198

    CAS  PubMed  Google Scholar 

  • Asanuma K, Yanagida-Asanuma E, Faul C, Tomino Y, Kim K, Mundel P (2006) Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol 8:485–491

    Article  CAS  PubMed  Google Scholar 

  • Beall B, Chalovich JM (2001) Fesselin, a synaptopodin-like protein, stimulates actin nucleation and polymerization. Biochemistry 40:14252–14259

    Article  CAS  PubMed  Google Scholar 

  • Beqqali A, Monshouwer-Kloots J, Monteiro R, Welling M, Bakkers J, Ehler E, Verkleij A, Mummery C, Passier R (2010) CHAP is a newly identified Z-disc protein essential for heart and skeletal muscle function. J Cell Sci 123:1141–1150

    Article  PubMed  Google Scholar 

  • Boggs JM, Rangaraj G (2000) Interaction of lipid-bound myelin basic protein with actin filaments and calmodulin. Biochemistry 39:7799–7806

    Article  CAS  PubMed  Google Scholar 

  • Buffa P, Manzella L, Consoli ML, Messina A, Vigneri P (2007) Modelling of the ABL and ARG proteins predicts two functionally critical regions that are natively unfolded. Proteins 67:1–11

    Article  CAS  PubMed  Google Scholar 

  • Campellone KG, Welch MD (2010) A nucleator arms race: cellular control of actin assembly. Nat Rev Mol Cell Biol 11:237–251

    Article  CAS  PubMed  Google Scholar 

  • Castano E, Philimonenko VV, Kahle M, Fukalova J, Kalendova A, Yildirim S, Dzijak R, Dingova-Krasna H, Hozak P (2010) Actin complexes in the cell nucleus: new stones in an old field. Histochem Cell Biol 133:607–626

    Article  CAS  PubMed  Google Scholar 

  • Cebrian V, Alvarez M, Aleman A, Palou J, Bellmunt J, Gonzalez-Peramato P, Cordon-Cardo C, Garcia J, Piulats JM, Sanchez-Carbayo M (2008) Discovery of myopodin methylation in bladder cancer. J Pathol 216:111–119

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Jiang ZG, Khan AA, Chishti AH, McKnight CJ (2009) Dematin exhibits a natively unfolded core domain and an independently folded headpiece domain. Protein Sci 18:629–636

    CAS  PubMed  Google Scholar 

  • Chen L, Yang S, Jakoncic J, Zhang JJ, Huang XY (2010) Migrastatin analogues target fascin to block tumour metastasis. Nature 464:1062–1066

    Article  CAS  PubMed  Google Scholar 

  • Claeys KG, van der Ven PF, Behin A, Stojkovic T, Eymard B, Dubourg O, Laforet P, Faulkner G, Richard P, Vicart P, Romero NB, Stoltenburg G, Udd B, Fardeau M, Voit T, Furst DO (2009) Differential involvement of sarcomeric proteins in myofibrillar myopathies: a morphological and immunohistochemical study. Acta Neuropathol 117:293–307

    Article  CAS  PubMed  Google Scholar 

  • De Ganck A, Hubert T, Van Impe K, Geelen D, Vandekerckhove J, De Corte V, Gettemans J (2005) A monopartite nuclear localization sequence regulates nuclear targeting of the actin binding protein myopodin. FEBS Lett 579:6673–6680

    Article  PubMed  CAS  Google Scholar 

  • De Ganck A, De Corte V, Staes A, Gevaert K, Vandekerckhove J, Gettemans J (2008) Multiple isoforms of the tumor suppressor myopodin are simultaneously transcribed in cancer cells. Biochem Biophys Res Commun 370:269–273

    Article  PubMed  CAS  Google Scholar 

  • De Ganck A, De Corte V, Bruyneel E, Bracke M, Vandekerckhove J, Gettemans J (2009) Down-regulation of myopodin expression reduces invasion and motility of PC-3 prostate cancer cells. Int J Oncol 34:1403–1409

    PubMed  Google Scholar 

  • Deller T, Korte M, Chabanis S, Drakew A, Schwegler H, Stefani GG, Zuniga A, Schwarz K, Bonhoeffer T, Zeller R, Frotscher M, Mundel P (2003) Synaptopodin-deficient mice lack a spine apparatus and show deficits in synaptic plasticity. Proc Natl Acad Sci USA 100:10494–10499

    Article  CAS  PubMed  Google Scholar 

  • Deller T, Orth CB, Del TD, Vlachos A, Burbach GJ, Drakew A, Chabanis S, Korte M, Schwegler H, Haas CA, Frotscher M (2007) A role for synaptopodin and the spine apparatus in hippocampal synaptic plasticity. Ann Anat 189:5–16

    CAS  PubMed  Google Scholar 

  • Dobrowolski Z, Osinska H, Mossakowska M, Barylko B (1986) Ca2 + -calmodulin-dependent polymerization of actin by myelin basic protein. Eur J Cell Biol 42:17–26

    CAS  PubMed  Google Scholar 

  • Dominguez R (2004) Actin-binding proteins - a unifying hypothesis. Trends Biochem Sci 29:572–578

    Article  CAS  PubMed  Google Scholar 

  • Donnelly SF, Pocklington MJ, Pallotta D, Orr E (1993) A proline-rich protein, verprolin, involved in cytoskeletal organization and cellular growth in the yeast Saccharomyces cerevisiae. Mol Microbiol 10:585–596

    Article  CAS  PubMed  Google Scholar 

  • Faul C, Hüttelmaier S, Oh J, Hachet V, Singer RH, Mundel P (2005) Promotion of importin alpha-mediated nuclear import by the phosphorylation-dependent binding of cargo protein to 14-3-3. J Cell Biol 169:415–424

    Article  CAS  PubMed  Google Scholar 

  • Faul C, Dhume A, Schecter AD, Mundel P (2007) Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes. Mol Cell Biol 27:8215–8227

    Article  CAS  PubMed  Google Scholar 

  • Fazal FM, Minhajuddin M, Bijli KM, McGrath JL, Rahman A (2007) Evidence for actin cytoskeleton-dependent and –independent pathways for RelA/p65 nuclear translocation in endothelial cells. J Biol Chem 282:3940–3950

    Article  CAS  PubMed  Google Scholar 

  • Galazkiewicz B, Mossakowska M, Osinska H, Dabrowska R (1985) Polymerization of G-actin by caldesmon. FEBS Lett 184:144–149

    Article  CAS  PubMed  Google Scholar 

  • Gieni RS, Hendzel MJ (2009) Actin dynamics and functions in the interphase nucleus: moving toward an understanding of nuclear polymeric actin. Biochem Cell Biol 87:283–306

    Article  CAS  PubMed  Google Scholar 

  • Iakoucheva LM, Brown CJ, Lawson JD, Obradovic Z, Dunker AK (2002) Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 323:573–584

    Article  CAS  PubMed  Google Scholar 

  • Iguchi T, Aishima S, Umeda K, Sanefuji K, Fujita N, Sugimachi K, Gion T, Taketomi A, Maehara Y, Tsuneyoshi M (2009) Fascin expression in progression and prognosis of hepatocellular carcinoma. J Surg Oncol 100:575–579

    Article  PubMed  Google Scholar 

  • Janmey PA (1994) Phosphoinosites and calcium as regulators of cellular actin assembly and disassembly. Annu Rev Physiol 56:169–191

    CAS  PubMed  Google Scholar 

  • Jing L, Liu L, Yu YP, Dhir R, Acquafondada M, Landsittel D, Cieply K, Wells A, Luo J-H (2004) Expression of myopodin induces suppression of tumor growth and metastasis, Am J Pathol 164:1799–1806

    Google Scholar 

  • Kaur GA, Delluc-Clavieres A, Poon IK, Forwood JK, Glover DJ, Jans DA (2010) Calmodulin-dependent nuclear import of HMG-box family nclear factors: importance of the role of SRY in sex reversal. Biochem J 430:39–48

    Article  CAS  PubMed  Google Scholar 

  • Khaymina SS, Kenney JM, Schroeter MM, Chalovich JM (2007) Fesselin is a natively unfolded protein. J Proteome Res 6:3648–3654

    Article  CAS  PubMed  Google Scholar 

  • Kleene R, Mzoughi M, Joshi G, Kalus I, Bormann U, Schulze C, Xiao MF, Dityatey A, Schachner M (2010) NCAM-induced neurite outgrowth depends on binding of calmodulin to NCAM and on nuclear import of NCAM and fak fragments. J Neurosci 30:10784–10798

    Article  CAS  PubMed  Google Scholar 

  • Kolakowski J, Wrzosek A, Dabrowska R (2004) Fesselin is a target protein for calmodulin in a calcium-dependent manner. Biochem Biophys Res Commun 323:1251–1256

    Article  CAS  PubMed  Google Scholar 

  • Kremerskothen J, Plaas C, Kindler S, Frotscher M, Barnekow A (2005) Synaptopodin, a molecule involved in the formation of the dendritic spine apparatus, is a dual actin/α-actinin binding protein. J Neurochem 92:597–606

    Article  CAS  PubMed  Google Scholar 

  • Le Gall T, Romero PR, Cortese MS, Uversky VN, Dunker AK (2007) Intrinsic disorder in the protein data bank. J Biomol Struct Dyn 24:325–342

    PubMed  Google Scholar 

  • Leinweber BD, Fredricksen RS, Hoffman DR, Chalovich JM (1999) Fesselin: a novel synaptopodin-like actin binding protein from muscle tissue. J Muscle Res Cell Motil 20:539–545

    Article  CAS  PubMed  Google Scholar 

  • Li A, Dawson JC, Forero-Vargas M, Spence HJ, Yu X, König I, Anderson K, Machesky LM (2010) The actin-bundling protein fascin stabilizes actin in invadopodia and potentiates protrusive invasion. Curr Biol 20:339–345

    Article  CAS  PubMed  Google Scholar 

  • Linnemann A, van der Ven PF, Vakeel P, Albinus B, Simonis D, Bendas G, Schenk JA, Micheel B, Kley RA, Furst DO (2010) The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and alpha-actinin. Eur J Cell Biol 89:681–692

    Article  CAS  PubMed  Google Scholar 

  • McGhee JD, von Hippel PH (1974) Theoretical aspects of DNA-protein interactions: co-operative and non-co-operative binding of large ligands to a one-dimensional homogeneous lattice. J Mol Biol 86:469–489

    Article  CAS  PubMed  Google Scholar 

  • Mundel P, Heid HW, Mundel TM, Krüger M, Reiser J, Kriz W (1997) Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes. J Cell Biol 139:193–204

    Article  CAS  PubMed  Google Scholar 

  • O'Neil KT, DeGrado WF (1990) How calmodulin binds its targets: sequence independent recognition of amphiphilic a-helicies. Trends Biochem Sci 15:59–64

    Article  PubMed  Google Scholar 

  • Papa I, Astier C, Kwiatek O, Raynaud F, Bonnal C, Lebart MC, Roustan C, Benyamin Y (1999) Alpha actinin-CapZ, an anchoring complex for thin filaments in Z-line. J Muscle Res Cell Motil 20:187–197

    Article  CAS  PubMed  Google Scholar 

  • Permyakov SE, Millett IS, Doniach S, Permyakov EA, Uversky VN (2003) Natively unfolded C-terminal domain of caldesmon remains substantially unstructured after the effective binding to calmodulin. Proteins 53:855–862

    Article  CAS  PubMed  Google Scholar 

  • Pham M, Chalovich JM (2006) Smooth muscle alpha-actinin binds tightly to fesselin and attenuates its activity toward actin polymerization. J Muscle Res Cell Motil 27:45–51

    Article  CAS  PubMed  Google Scholar 

  • Renegar RH, Chalovich JM, Leinweber BD, Zary JT, Schroeter MM (2009) Localization of the actin-binding protein fesselin in chicken smooth muscle. Histochem Cell Biol 131:191–196

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Carbayo M, Schwarz K, Charytonowicz E, Cordon-Cardo C, Mundel P (2003) Tumor suppressor role for myopodin in bladder cancer: loss of nuclear expression of myopodin is cell-cycle dependent and predicts clinical outcome. Oncogene 22:5298–5305

    Article  CAS  PubMed  Google Scholar 

  • Schaeffer G, Levak-Frank S, Spitaler MM, Fleischhacker E, Esenabhalu VE, Wagner AH, Hecker M, Graier WF (2003) Intercellular signalling within vascular cells under high D-glucose involves free radical-triggered tyrosine kinase activation. Diabetologia 46:773–783

    Article  CAS  PubMed  Google Scholar 

  • Schroeter M, Chalovich JM (2004) Ca2+-calmodulin regulates fesselin-induced actin polymerization. Biochemistry 43:13875–13882

    Article  CAS  PubMed  Google Scholar 

  • Schroeter MM, Chalovich JM (2005) Fesselin binds to actin and myosin and inhibits actin activated ATPase activity. J Muscle Res Cell Motil 26:183–189

    Article  CAS  PubMed  Google Scholar 

  • Schroeter MM, Beall B, Heid HW, Chalovich JM (2008) The actin binding protein, fesselin, is a member of the synaptopodin family. Biochem Biophys Res Commun 371:582–586

    Article  CAS  PubMed  Google Scholar 

  • Schroeter MM, Orlova A, Beall B, Egelman EH, Chalovich JM (2010) Organization of F-actin by avian smooth muscle synaptopodin 2 (fesselin). Biophys J 98:157a

    Article  Google Scholar 

  • Shen X, Valencia CA, Szostak J, Dong B, Liu R (2005) Scanning the human proteome for calmodulin-binding proteins. Proc Natl Acad Sci USA 102:5969–5974

    Article  CAS  PubMed  Google Scholar 

  • Shoemaker BA, Portman JJ, Wolynes PG (2000) Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc Natl Acad Sci USA 97:8868–8873

    Article  CAS  PubMed  Google Scholar 

  • Sickmeier M, Hamilton JA, Le Gall T, Vacic V, Cortese MS, Tantos A, Szabo B, Tompa P, Chen J, Uversky VN, Obradovic Z, Dunker AK (2007) DisProt: the database of disordered proteins. Nucleic Acids Res 35:D786–D793

    Article  CAS  PubMed  Google Scholar 

  • Tapp H, Al Naggar IM, Yarmola EG, Harrison A, Shaw G, Edison AS, Bubb MR (2005) MARCKS is a natively unfolded protein with an inaccessible actin-binding site: evidence for long-range intramolecular interactions. J Biol Chem 280:9946–9956

    Article  CAS  PubMed  Google Scholar 

  • Tompa P (2009) Structure and function of intrinsically disordered proteins. Taylor and Francis, Boca Raton, Fl

    Book  Google Scholar 

  • Tompa P, Fuxreiter M (2008) Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci 33:2–8

    Google Scholar 

  • Van Impe K, De Corte V, Eichinger L, Bruyneel E, Mareel M, Vandekerckhove J, Gettemans J (2003) The Nucleo-cytoplasmic actin-binding protein CapG lacks a nuclear export sequence present in structurally related proteins. J Biol Chem 278:17945–17952

    Article  PubMed  CAS  Google Scholar 

  • Vasioukhin V, Bauer C, Yin M, Fuchs E (2000) Directed actin polymerization is the driving force for epithelial cell-cell adhesion. Cell 100:209–219

    Article  CAS  PubMed  Google Scholar 

  • Vignjevic D, Schoumacher M, Gavert N, Janssen KP, Jih G, Laé M, Louvard D, Ben-Ze'ev A, Robine S (2007) Fascin, a novel target of beta-catenin-TCF signaling, is expressed at the invasive front of human colon cancer. Cancer Res 67:6844–6853

    Article  CAS  PubMed  Google Scholar 

  • Weins A, Schwarz K, Faul C, Barisoni L, Linke WA, Mundel P (2001) Differentiation- and stress-dependent nuclear cytoplasmic redistribution of myopodin, a novel actin-bundling protein. J Cell Biol 155:393–404

    Article  CAS  PubMed  Google Scholar 

  • Yanagida-Asanuma E, Asanuma K, Kim K, Donnelly M, Young CH, Hyung CJ, Suetsugu S, Tomino Y, Takenawa T, Faul C, Mundel P (2007) Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes. Am J Pathol 171:415–427

    Article  CAS  PubMed  Google Scholar 

  • Yu YP, Luo JH (2006) Myopodin-mediated suppression of prostate cancer cell migration involves interaction with zyxin. Cancer Res 66:7414–7419

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded by grant AR035216 from the National Institutes of Health (to J.M.C.) and a grant from the Brody Brothers Endowment (J.M.C. and M.M.S.).

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Correspondence to Joseph M. Chalovich.

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Chalovich, J.M., Schroeter, M.M. Synaptopodin family of natively unfolded, actin binding proteins: physical properties and potential biological functions. Biophys Rev 2, 181–189 (2010). https://doi.org/10.1007/s12551-010-0040-5

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