Microfibrils and Fibrillin

Chapter
Part of the Biology of Extracellular Matrix book series (BEM)

Abstract

Microfibrils are supramolecular structures ubiquitously found in the extracellular matrix of elastic and nonelastic tissues. The three members of the cysteine-rich fibrillin family constitute the core of microfibrils. Mutations in fibrillin-1 and -2 lead to a number of heritable connective tissue disorders termed fibrillinopathies. Clinical symptoms affect blood vessels, bone, the eye, and other organ systems and highlight the importance of fibrillins in development and homeostasis of tissues and organs. Microfibrils have functional significance (1) in conferring mechanical stability and limited elasticity to tissues; (2) in the biogenesis and maintenance of the elastic fiber system; and (3) in the modulation of the activity of growth factors, including transforming growth factor-β and several bone morphogenetic proteins. In this chapter, we provide an overview of the structure, assembly, and functions of fibrillins and microfibrils and also the pathobiology associated with genetic aberrations in the microfibril system. Lessons learned from mouse models will be discussed as well as the emerging role of microfibrils and fibrillins in the regulation of growth factor bioavailability. Due to the large number of articles in the field, we repeatedly cite excellent review articles to which interested readers are referred to for more details.

Abbreviations

BMP

Bone morphogenetic protein

cbEGF

Calcium-binding epidermal growth factor like domain

CCA

Congenital contractural arachnodactyly

EGF

Epidermal growth factor like domain

FBN1

Human fibrillin-1 gene

Fbn1

Mouse fibrillin-1 gene

FBN2

Human fibrillin-2 gene

Fbn2

Mouse fibrillin-2 gene

LTBP

Latent transforming growth factor-β binding protein

TGF-β

Transforming growth factor-β

Tsk

Tight-skin mutation

References

  1. Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116:217–224PubMedCrossRefGoogle Scholar
  2. Arteaga-Solis E, Gayraud B, Lee SY, Shum L, Sakai LY, Ramirez F (2001) Regulation of limb patterning by extracellular microfibrils. J Cell Biol 154:275–281PubMedCrossRefGoogle Scholar
  3. Ashworth JL, Kelly V, Wilson R, Shuttleworth CA, Kielty CM (1999) Fibrillin assembly: dimer formation mediated by amino-terminal sequences. J Cell Sci 112:3549–3558PubMedGoogle Scholar
  4. Baldock C, Koster AJ, Ziese U, Rock MJ, Sherratt MJ, Kadler KE, Shuttleworth CA, Kielty CM (2001) The supramolecular organization of fibrillin-rich microfibrils. J Cell Biol 152:1045–1056PubMedCrossRefGoogle Scholar
  5. Bax DV, Bernard SE, Lomas A, Morgan A, Humphries J, Shuttleworth A, Humphries MJ, Kielty CM (2003) Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by alpha5 beta1 and alphav beta3 integrins. J Biol Chem 278:34605–34616PubMedCrossRefGoogle Scholar
  6. Bowness JM, Tarr AH (1997) Epsilon(gamma-Glutamyl)lysine crosslinks are concentrated in a non-collagenous microfibrillar fraction of cartilage. Biochem Cell Biol 75:89–91PubMedCrossRefGoogle Scholar
  7. Bressan GM, Daga-Gordini D, Colombatti A, Castellani I, Marigo V, Volpin D (1993) Emilin, a component of elastic fibers preferentially located at the elastin-microfibril interface. J Cell Biol 121:201–212PubMedCrossRefGoogle Scholar
  8. Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC (2008) Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med 358:2787–2795PubMedCrossRefGoogle Scholar
  9. Cain SA, Baldock C, Gallagher J, Morgan A, Bax DV, Weiss AS, Shuttleworth CA, Kielty CM (2005) Fibrillin-1 interactions with heparin: implications for microfibril and elastic fibre assembly. J Biol Chem 280:30526–30537PubMedCrossRefGoogle Scholar
  10. Cain SA, Morgan A, Sherratt MJ, Ball SG, Shuttleworth CA, Kielty CM (2006) Proteomic analysis of fibrillin-rich microfibrils. Proteomics 6:111–122PubMedCrossRefGoogle Scholar
  11. Callewaert BL, Loeys BL, Ficcadenti A, Vermeer S, Landgren M, Kroes HY, Yaron Y, Pope M, Foulds N, Boute O, Galan F, Kingston H, Van der Aa N, Salcedo I, Swinkels ME, Wallgren-Pettersson C, Gabrielli O, De BJ, Coucke PJ, De Paepe AM (2009) Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations and review of the literature. Hum Mutat 30:334–341PubMedCrossRefGoogle Scholar
  12. Carta L, Pereira L, Arteaga-Solis E, Lee-Arteaga SY, Lenart B, Starcher B, Merkel CA, Sukoyan M, Kerkis A, Hazeki N, Keene DR, Sakai LY, Ramirez F (2006) Fibrillins 1 and 2 perform partially overlapping functions during aortic development. J Biol Chem 281:8016–8023PubMedCrossRefGoogle Scholar
  13. Charbonneau NL, Dzamba BJ, Ono RN, Keene DR, Corson GM, Reinhardt DP, Sakai LY (2003) Fibrillins can co-assemble in fibrils, but fibrillin fibril composition displays cell-specific differences. J Biol Chem 278:2740–2749PubMedCrossRefGoogle Scholar
  14. Charbonneau NL, Ono RN, Corson GM, Keene DR, Sakai LY (2004) Fine tuning of growth factor signals depends on fibrillin microfibril networks. Birth Defects Res C Embryo Today 72:37–50PubMedCrossRefGoogle Scholar
  15. Chaudhry SS, Gazzard J, Baldock C, Dixon J, Rock MJ, Skinner GC, Steel KP, Kielty CM, Dixon MJ (2001) Mutation of the gene encoding fibrillin-2 results in syndactyly in mice. Hum Mol Genet 10:835–843PubMedCrossRefGoogle Scholar
  16. Chaudhry SS, Cain SA, Morgan A, Dallas SL, Shuttleworth CA, Kielty CM (2007) Fibrillin-1 regulates the bioavailability of TGF-beta1. J Cell Biol 176:355–367PubMedCrossRefGoogle Scholar
  17. Chen Y, Ali T, Todorovic V, O’Leary JM, Kristina DA, Rifkin DB (2005) Amino acid requirements for formation of the TGF-beta-latent TGF-beta binding protein complexes. J Mol Biol 345:175–186PubMedCrossRefGoogle Scholar
  18. Choudhury R, McGovern A, Ridley C, Cain SA, Baldwin A, Wang M-C, Guo C, Mironov AJ, Drymoussi Z, Trump D, Shuttleworth A, Baldock C, Kielty CM (2009) Differential regulation of elastic fiber formation by fibulins-4 and -5. J Biol Chem 284:24553–24567PubMedCrossRefGoogle Scholar
  19. Cohn RD, van EC H, JP SAA, Klein EC, Lisi MT, Gamradt M, ap Rhys CM, Holm TM, Loeys BL, Ramirez F, Judge DP, Ward CW, Dietz HC (2007) Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med 13:204–210PubMedCrossRefGoogle Scholar
  20. Collod-Beroud G, Le Bourdelles S, Ades L, Ala-Kokko L, Booms P, Boxer M, Child A, Comeglio P, De Paepe A, Hyland JC, Holman K, Kaitila I, Loeys B, Matyas G, Nuytinck L, Peltonen L, Rantamaki T, Robinson P, Steinmann B, Junien C, Beroud C, Boileau C (2003) Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 22:199–208PubMedCrossRefGoogle Scholar
  21. Corson GM, Chalberg SC, Dietz HC, Charbonneau NL, Sakai LY (1993) Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain structure and alternatively spliced exons at the 5′ end. Genomics 17:476–484PubMedCrossRefGoogle Scholar
  22. Corson GM, Charbonneau NL, Keene DR, Sakai LY (2004) Differential expression of fibrillin-3 adds to microfibril variety in human and avian, but not rodent, connective tissues. Genomics 83:461–472PubMedCrossRefGoogle Scholar
  23. Dallas SL, Keene DR, Bruder SP, Saharinen J, Sakai LY, Mundy GR, Bonewald LF (2000) Role of the latent transforming growth factor beta binding protein 1 in fibrillin-containing microfibrils in bone cells in vitro and in vivo. J Bone Miner Res 15:68–81PubMedCrossRefGoogle Scholar
  24. Dallas SL, Sivakumar P, Jones CJ, Chen Q, Peters DM, Mosher DF, Humphries MJ, Kielty CM (2005) Fibronectin regulates latent transforming growth factor-beta (TGF beta) by controlling matrix assembly of latent TGF beta-binding protein-1. J Biol Chem 280:18871–18880PubMedCrossRefGoogle Scholar
  25. Davis EC, Roth RA, Heuser JE, Mecham RP (2002) Ultrastructural properties of ciliary zonule microfibrils. J Struct Biol 139:65–75PubMedCrossRefGoogle Scholar
  26. Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, Stetten G, Meyers DA, Francomano CA (1991) Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352:337–339PubMedCrossRefGoogle Scholar
  27. Downing AK, Knott V, Werner JM, Cardy CM, Campbell ID, Handford PA (1996) Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders. Cell 85:597–605PubMedCrossRefGoogle Scholar
  28. Dudley AT, Lyons KM, Robertson EJ (1995) A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev 9:2795–2807PubMedCrossRefGoogle Scholar
  29. El-Hallous E, Sasaki T, Hubmacher D, Getie M, Tiedemann K, Brinckmann J, Bätge B, Davis EC, Reinhardt DP (2007) Fibrillin-1 interactions with fibulins depend on the first hybrid domain and provide an adapter function to tropoelastin. J Biol Chem 282:8935–8946PubMedCrossRefGoogle Scholar
  30. Eriksen TA, Wright DM, Purslow PP, Duance VC (2001) Role of Ca(2+) for the mechanical properties of fibrillin. Proteins 45:90–95PubMedCrossRefGoogle Scholar
  31. Fahrenbach WH, Sandberg LB, Cleary EG (1966) Ultrastructural studies on early elastogenesis. Anat Rec 155:563–576CrossRefGoogle Scholar
  32. Faivre L, Dollfus H, Lyonnet S, Alembik Y, Megarbane A, Samples J, Gorlin RJ, Alswaid A, Feingold J, Le MM, Munnich A, Cormier-Daire V (2003a) Clinical homogeneity and genetic heterogeneity in Weill–Marchesani syndrome. Am J Med Genet A 123:204–207CrossRefGoogle Scholar
  33. Faivre L, Gorlin RJ, Wirtz MK, Godfrey M, Dagoneau N, Samples JR, Le MM, Collod-Beroud G, Boileau C, Munnich A, Cormier-Daire V (2003b) In frame fibrillin-1 gene deletion in autosomal dominant Weill–Marchesani syndrome. J Med Genet 40:34–36PubMedCrossRefGoogle Scholar
  34. Faivre L, Collod-Beroud G, Loeys BL, Child A, Binquet C, Gautier E, Callewaert B, Arbustini E, Mayer K, Arslan-Kirchner M, Kiotsekoglou A, Comeglio P, Marziliano N, Dietz HC, Halliday D, Beroud C, Bonithon-Kopp C, Claustres M, Muti C, Plauchu H, Robinson PN, Ades LC, Biggin A, Benetts B, Brett M, Holman KJ, de Backer J, Coucke P, Francke U, De Paepe A, Jondeau G, Boileau C (2007) Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 81:454–466PubMedCrossRefGoogle Scholar
  35. Fleischer KJ, Nousari HC, Anhalt GJ, Stone CD, Laschinger JC (1997) Immunohistochemical abnormalities of fibrillin in cardiovascular tissues in Marfan’s syndrome. Ann Thorac Surg 63:1012–1017PubMedCrossRefGoogle Scholar
  36. Frederic MY, Monino C, Marschall C, Hamroun D, Faivre L, Jondeau G, Klein HG, Neumann L, Gautier E, Binquet C, Maslen C, Godfrey M, Gupta P, Milewicz D, Boileau C, Claustres M, Beroud C, Collod-Beroud G (2009) The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations. Hum Mutat 30:181–190PubMedCrossRefGoogle Scholar
  37. Gayraud B, Keene DR, Sakai LY, Ramirez F (2000) New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin 1 mutation in the tight skin mouse. J Cell Biol 150:667–680PubMedCrossRefGoogle Scholar
  38. Ge G, Greenspan DS (2006) BMP1 controls TGFbeta1 activation via cleavage of latent TGFbeta-binding protein 6. J Cell Biol 175:111–120PubMedCrossRefGoogle Scholar
  39. Gentry LE, Lioubin MN, Purchio AF, Marquardt H (1988) Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. Mol Cell Biol 8:4162–4168PubMedGoogle Scholar
  40. Gibson MA, Kumaratilake JS, Cleary EG (1989) The protein components of the 12-nanometer microfibrils of elastic and nonelastic tissues. J Biol Chem 264:4590–4598PubMedGoogle Scholar
  41. Gibson MA, Hatzinikolas G, Davis EC, Baker E, Sutherland GR, Mecham RP (1995) Bovine latent transforming growth factor beta 1-binding protein 2: molecular cloning, identification of tissue isoforms, and immunolocalization to elastin-associated microfibrils. Mol Cell Biol 15:6932–6942PubMedGoogle Scholar
  42. Giltay R, Timpl R, Kostka G (1999) Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4. Matrix Biol 18:469–480PubMedCrossRefGoogle Scholar
  43. Giusti B, Porciani MC, Brunelli T, Evangelisti L, Fedi S, Gensini GF, ABbate R, Sani G, Yacoub M, Pepe G (2003) Phenotypic variability of cardiovascular manifestations in Marfan Syndrome. Possible role of hyperhomocysteinemia and C677T MTHFR gene polymorphism. Eur Heart J 24:2038–2045PubMedCrossRefGoogle Scholar
  44. Gleizes PE, Beavis RC, Mazzieri R, Shen B, Rifkin DB (1996) Identification and characterization of an eight-cysteine repeat of the latent transforming growth factor-beta binding protein-1 that mediates bonding to the latent transforming growth factor-beta1. J Biol Chem 271:29891–29896PubMedCrossRefGoogle Scholar
  45. Glushchenko AV, Jacobsen DW (2007) Molecular targeting of proteins by l-homocysteine: mechanistic implications for vascular disease. Antioxid Redox Signal 9:1883–1898PubMedCrossRefGoogle Scholar
  46. Green MC, Sweet HO, Bunker LE (1976) Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am J Pathol 82:493–512PubMedGoogle Scholar
  47. Greenlee TK, Ross R, Hartman JL (1966) The fine structure of elastic fibers. J Cell Biol 30:59–71PubMedCrossRefGoogle Scholar
  48. Gregory KE, Ono RN, Charbonneau NL, Kuo CL, Keene DR, Bächinger HP, Sakai LY (2005) The prodomain of BMP-7 targets the BMP-7 complex to the extracellular matrix. J Biol Chem 280:27970–27980PubMedCrossRefGoogle Scholar
  49. Gupta PA, Putnam EA, Carmical SG, Kaitila I, Steinmann B, Child A, Danesino C, Metcalfe K, Berry SA, Chen E, Delorme CV, Thong MK, Ades LC, Milewicz DM (2002) Ten novel FBN2 mutations in congenital contractural arachnodactyly: delineation of the molecular pathogenesis and clinical phenotype. Hum Mutat 19:39–48PubMedCrossRefGoogle Scholar
  50. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC (2006) Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312:117–121PubMedCrossRefGoogle Scholar
  51. Halme T, Savunen T, Aho H, Vihersaari T, Penttinen R (1985) Elastin and collagen in the aortic wall: changes in the Marfan syndrome and annuloaortic ectasia. Exp Mol Pathol 43:1–12PubMedCrossRefGoogle Scholar
  52. Handford PA (2000) Fibrillin-1, a calcium binding protein of extracellular matrix. Biochim Biophys Acta 1498:84–90PubMedCrossRefGoogle Scholar
  53. Handford PA, Mayhew M, Baron M, Winship PR, Campbell ID, Brownlee GG (1991) Key residues involved in calcium-binding motifs in EGF-like domains. Nature 351:164–167PubMedCrossRefGoogle Scholar
  54. Hertwig P (1942) Neue Mutationen und Koppelungsgruppen bei der Hausmaus. Z Indukt Abstamm Vererbungsl 80:220–246CrossRefGoogle Scholar
  55. Hill CH, Mecham R, Starcher B (2002) Fibrillin-2 defects impair elastic fiber assembly in a homocysteinemic chick model. J Nutr 132:2143–2150PubMedGoogle Scholar
  56. Hubmacher D, Tiedemann K, Bartels R, Brinckmann J, Vollbrandt T, Bätge B, Notbohm H, Reinhardt DP (2005) Modification of the structure and function of fibrillin-1 by homocysteine suggests a potential pathogenetic mechanism in homocystinuria. J Biol Chem 280:34946–34955PubMedCrossRefGoogle Scholar
  57. Hubmacher D, Tiedemann K, Reinhardt DP (2006) Fibrillins: from biogenesis of microfibrils to signaling functions. Curr Top Dev Biol 75:93–123PubMedCrossRefGoogle Scholar
  58. Hubmacher D, El-Hallous E, Nelea V, Kaartinen MT, Lee ER, Reinhardt DP (2008) Biogenesis of extracellular microfibrils – multimerization of the fibrillin-1 C-terminus into bead-like structures enables self-assembly. Proc Natl Acad Sci USA 105:6548–6553PubMedCrossRefGoogle Scholar
  59. Hubmacher D, Cirulis JT, Miao M, Keeley FW, Reinhardt DP (2010) Functional consequences of homocysteinylation of the elastic fiber proteins fibrillin-1 and tropoelastin. J Biol Chem 285:1188–1198PubMedCrossRefGoogle Scholar
  60. Hutchinson S, Aplin RT, Webb H, Kettle S, Timmermans J, Boers GH, Handford PA (2005) Molecular effects of homocysteine on cbEGF domain structure: insights into the pathogenesis of homocystinuria. J Mol Biol 346:833–844PubMedCrossRefGoogle Scholar
  61. Hyytiäinen M, Penttinen C, Keski-Oja J (2004) Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activation. Crit Rev Clin Lab Sci 41:233–264PubMedCrossRefGoogle Scholar
  62. Isogai Z, Ono RN, Ushiro S, Keene DR, Chen Y, Mazzieri R, Charbonneau NL, Reinhardt DP, Rifkin DB, Sakai LY (2003) Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J Biol Chem 278:2750–2757PubMedCrossRefGoogle Scholar
  63. Jensen SA, Corbett AR, Knott V, Redfield C, Handford PA (2005) Ca2+-dependent interface formation in fibrillin-1. J Biol Chem 280:14076–14084PubMedCrossRefGoogle Scholar
  64. Jensen SA, Iqbal S, Lowe ED, Redfield C, Handford PA (2009) Structure and interdomain interactions of a hybrid domain: a disulphide-rich module of the fibrillin/LTBP superfamily of matrix proteins. Structure 17:759–768PubMedCrossRefGoogle Scholar
  65. Johnson KR, Cook SA, Zheng QY (1998) The original shaker-with-syndactylism mutation (sy) is a contiguous gene deletion syndrome. Mamm Genome 9:889–892PubMedCrossRefGoogle Scholar
  66. Jovanovic J, Takagi J, Choulier L, Abrescia NG, Stuart DI, van der Merwe PA, Mardon HJ, Handford PA (2007) Alpha v beta 6 is a novel receptor for human fibrillin-1: comparative studies of molecular determinants underlying integrin-RGD affinity and specificity. J Biol Chem 282:6743–6751PubMedCrossRefGoogle Scholar
  67. Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC (2004) Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 114:172–181PubMedGoogle Scholar
  68. Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L (1990) Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 323:935–939PubMedCrossRefGoogle Scholar
  69. Kantola AK, Keski-Oja J, Koli K (2008) Fibronectin and heparin binding domains of latent TGF-beta binding protein (LTBP)-4 mediate matrix targeting and cell adhesion. Exp Cell Res 314:2488–2500PubMedCrossRefGoogle Scholar
  70. Keene DR, Maddox BK, Kuo HJ, Sakai LY, Glanville RW (1991) Extraction of extendable beaded structures and their identification as fibrillin-containing extracellular matrix microfibrils. J Histochem Cytochem 39:441–449PubMedGoogle Scholar
  71. Keene DR, Jordan CD, Reinhardt DP, Ridgway CC, Ono RN, Corson GM, Fairhurst M, Sussman MD, Memoli VA, Sakai LY (1997) Fibrillin-1 in human cartilage: developmental expression and formation of special banded fibers. J Histochem Cytochem 45:1069–1082PubMedGoogle Scholar
  72. Kielty CM, Phillips JE, Child AH, Pope FM, Shuttleworth CA (1994) Fibrillin secretion and microfibril assembly by Marfan dermal fibroblasts. Matrix Biol 14:191–199PubMedCrossRefGoogle Scholar
  73. Kielty CM, Raghunath M, Siracusa LD, Sherratt MJ, Peters R, Shuttleworth CA, Jimenez SA (1998) The tight skin mouse: demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils. J Cell Biol 140:1159–1166PubMedCrossRefGoogle Scholar
  74. Kinsey R, Williamson MR, Chaudhry S, Mellody KT, McGovern A, Takahashi S, Shuttleworth CA, Kielty CM (2008) Fibrillin-1 microfibril deposition is dependent on fibronectin assembly. J Cell Sci 121:2696–2704PubMedCrossRefGoogle Scholar
  75. Koli K, Hyytiäinen M, Ryynanen MJ, Keski-Oja J (2005) Sequential deposition of latent TGF-beta binding proteins (LTBPs) during formation of the extracellular matrix in human lung fibroblasts. Exp Cell Res 310:370–382PubMedCrossRefGoogle Scholar
  76. Kriz W, Elger M, Lemley K, Sakai T (1990) Structure of the glomerular mesangium: a biomechanical interpretation. Kidney Int Suppl 30:S2–S9PubMedGoogle Scholar
  77. Krumdieck CL, Prince CW (2000) Mechanisms of homocysteine toxicity on connective tissues: implications for the morbidity of aging. J Nutr 130:365S–368SPubMedGoogle Scholar
  78. Kuo CL, Isogai Z, Keene DR, Hazeki N, Ono RN, Sengle G, Bächinger HP, Sakai LY (2007) Effects of fibrillin-1 degradation on microfibril ultrastructure. J Biol Chem 282:4007–4020PubMedCrossRefGoogle Scholar
  79. Lee B, Godfrey M, Vitale E, Hori H, Mattei MG, Sarfarazi M, Tsipouras P, Ramirez F, Hollister DW (1991) Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 352:330–334PubMedCrossRefGoogle Scholar
  80. Lee SS, Knott V, Jovanovic J, Harlos K, Grimes JM, Choulier L, Mardon HJ, Stuart DI, Handford PA (2004) Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization. Structure (Camb) 12:717–729CrossRefGoogle Scholar
  81. Lemaire R, Bayle J, Lafyatis R (2006) Fibrillin in Marfan syndrome and tight skin mice provides new insights into transforming growth factor-beta regulation and systemic sclerosis. Curr Opin Rheumatol 18:582–587PubMedCrossRefGoogle Scholar
  82. Lin G, Tiedemann K, Vollbrandt T, Peters H, Bätge B, Brinckmann J, Reinhardt DP (2002) Homo- and heterotypic fibrillin-1 and -2 interactions constitute the basis for the assembly of microfibrils. J Biol Chem 277:50795–50804PubMedCrossRefGoogle Scholar
  83. Loeys BL, Gerber EE, Riegert-Johnson D, Iqbal S, Whiteman P, McConnell V, Chillakuri CR, Macaya D, Coucke PJ, De Paepe A, Judge DP, Wigley F, Davis EC, Mardon HJ, Handford P, Keene DR, Sakai LY, Dietz HC (2010) Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci Transl Med 2:23ra20PubMedGoogle Scholar
  84. Low FN (1962) Microfibrils: fine filamentous components of the tissue space. Anat Rec 142:131–137PubMedCrossRefGoogle Scholar
  85. Luo G, Hofmann C, Bronckers AL, Sohocki M, Bradley A, Karsenty G (1995) BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev 9:2808–2820PubMedCrossRefGoogle Scholar
  86. Marson A, Rock MJ, Cain SA, Freeman LJ, Morgan A, Mellody K, Shuttleworth CA, Baldock C, Kielty CM (2005) Homotypic fibrillin-1 interactions in microfibril assembly. J Biol Chem 280:5013–5021PubMedCrossRefGoogle Scholar
  87. Maslen CL, Corson GM, Maddox BK, Glanville RW, Sakai LY (1991) Partial sequence of a candidate gene for the Marfan syndrome. Nature 352:334–337PubMedCrossRefGoogle Scholar
  88. McConnell CJ, Wright GM, DeMont ME (1996) The modulus of elasticity of lobster aorta microfibrils. Experientia 52:918–921PubMedCrossRefGoogle Scholar
  89. Milewicz D, Pyeritz RE, Crawford ES, Byers PH (1992) Marfan syndrome: defective synthesis, secretion, and extracellular matrix formation of fibrillin by cultured dermal fibroblasts. J Clin Invest 89:79–86PubMedCrossRefGoogle Scholar
  90. Milewicz DM, Grossfield J, Cao SN, Kielty C, Covitz W, Jewett T (1995) A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome. J Clin Invest 95:2373–2378PubMedCrossRefGoogle Scholar
  91. Miyazono K, Olofsson A, Colosetti P, Heldin CH (1991) A role of the latent TGF-β1-binding protein in the assembly and secretion of TGF-β1. EMBO J 10:1091–1101PubMedGoogle Scholar
  92. Nagase T, Nakayama M, Nakajima D, Kikuno R, Ohara O (2001) Prediction of the coding sequences of unidentified human genes. XXII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 8:85–95PubMedCrossRefGoogle Scholar
  93. Nakajima Y, Miyazono K, Kato M, Takase M, Yamagishi T, Nakamura H (1997) Extracellular fibrillar structure of latent TGF beta binding protein-1: role in TGF beta-dependent endothelial-mesenchymal transformation during endocardial cushion tissue formation in mouse embryonic heart. J Cell Biol 136:193–204PubMedCrossRefGoogle Scholar
  94. Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC (2003) Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 33:407–411PubMedCrossRefGoogle Scholar
  95. Ono RN, Sengle G, Charbonneau NL, Carlberg V, Bachinger HP, Sasaki T, Lee-Arteaga S, Zilberberg L, Rifkin DB, Ramirez F, Chu ML, Sakai LY (2009) Latent transforming growth factor beta-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites. J Biol Chem 284:16872–16881PubMedCrossRefGoogle Scholar
  96. Park ES, Putnam EA, Chitayat D, Child A, Milewicz DM (1998) Clustering of FBN2 mutations in patients with congenital contractural arachnodactyly indicates an important role of the domains encoded by exons 24 through 34 during human development. Am J Med Genet 78:350–355PubMedCrossRefGoogle Scholar
  97. Pereira L, D’Alessio M, Ramirez F, Lynch JR, Sykes B, Pangilinan T, Bonadio J (1993) Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome. Hum Mol Genet 2:961–968PubMedCrossRefGoogle Scholar
  98. Pereira L, Andrikopoulos K, Tian J, Lee SY, Keene DR, Ono RN, Reinhardt DP, Sakai LY, Jensen-Biery N, Bunton T, Dietz HC, Ramirez F (1997) Targeting of fibrillin-1 recapitulates the vascular phenotype of Marfan syndrome in the mouse. Nat Genet 17:218–222PubMedCrossRefGoogle Scholar
  99. Pereira L, Lee SY, Gayraud B, Andrikopoulos K, Shapiro SD, Bunton T, Biery NJ, Dietz HC, Sakai LY, Ramirez F (1999) Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci USA 96:3819–3823PubMedCrossRefGoogle Scholar
  100. Pfaff M, Reinhardt DP, Sakai LY, Timpl R (1996) Cell adhesion and integrin binding to recombinant human fibrillin-1. FEBS Lett 384:247–250PubMedCrossRefGoogle Scholar
  101. Putnam EA, Zhang H, Ramirez F, Milewicz DM (1995) Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet 11:456–458PubMedCrossRefGoogle Scholar
  102. Pyeritz RE (2000) The Marfan syndrome. Annu Rev Med 51:481–510PubMedCrossRefGoogle Scholar
  103. Qian RQ, Glanville RW (1997) Alignment of fibrillin molecules in elastic microfibrils is defined by transglutaminase-derived cross-links. Biochemistry 36:15841–15847PubMedCrossRefGoogle Scholar
  104. Quondamatteo F, Reinhardt DP, Charbonneau NL, Pophal G, Sakai LY, Herken R (2002) Fibrillin-1 and fibrillin-2 in human embryonic and early fetal development. Matrix Biol 21:637–646PubMedCrossRefGoogle Scholar
  105. Raghunath M, Bächi T, Meuli M, Altermatt S, Gobet R, Bruckner-Tuderman L, Steinmann B (1996) Fibrillin and elastin expression in skin regenerating from cultured keratinocyte autografts: morphogenesis of microfibrils begins at the dermo-epidermal junction and precedes elastic fiber formation. J Invest Dermatol 106:1090–1095PubMedCrossRefGoogle Scholar
  106. Raghunath M, Unsöld C, Kubitscheck U, Bruckner-Tuderman L, Peters R, Meuli M (1998) The cutaneous microfibrillar apparatus contains latent transforming growth factor-beta binding protein-1 (LTBP-1) and is a repository for latent TGF-beta1. J Invest Dermatol 111:559–564PubMedCrossRefGoogle Scholar
  107. Ramirez F, Rifkin DB (2009) Extracellular microfibrils: contextual platforms for TGF-beta and BMP signaling. Curr Opin Cell Biol 21:616–622PubMedCrossRefGoogle Scholar
  108. Ramirez F, Sakai LY (2010) Biogenesis and function of fibrillin assemblies. Cell Tissue Res 339:71–82PubMedCrossRefGoogle Scholar
  109. Ramirez F, Carta L, Lee-Arteaga S, Liu C, Nistala H, Smaldone S (2008) Fibrillin-rich microfibrils – structural and instructive determinants of mammalian development and physiology. Connect Tissue Res 49:1–6PubMedCrossRefGoogle Scholar
  110. Raviola G (1971) The fine structure of the ciliary zonule and ciliary epithelium. Invest Ophthalmol 10:851–869PubMedGoogle Scholar
  111. Reinhardt DP, Sasaki T, Dzamba BJ, Keene DR, Chu ML, Göhring W, Timpl R, Sakai LY (1996a) Fibrillin-1 and fibulin-2 interact and are colocalized in some tissues. J Biol Chem 271:19489–19496PubMedCrossRefGoogle Scholar
  112. Reinhardt DP, Keene DR, Corson GM, Pöschl E, Bächinger HP, Gambee JE, Sakai LY (1996b) Fibrillin 1: organization in microfibrils and structural properties. J Mol Biol 258:104–116PubMedCrossRefGoogle Scholar
  113. Reinhardt DP, Ono RN, Sakai LY (1997a) Calcium stabilizes fibrillin-1 against proteolytic degradation. J Biol Chem 272:1231–1236PubMedCrossRefGoogle Scholar
  114. Reinhardt DP, Mechling DE, Boswell BA, Keene DR, Sakai LY, Bächinger HP (1997b) Calcium determines the shape of fibrillin. J Biol Chem 272:7368–7373PubMedCrossRefGoogle Scholar
  115. Reinhardt DP, Gambee JE, Ono RN, Bächinger HP, Sakai LY (2000) Initial steps in assembly of microfibrils. Formation of disulfide-cross-linked multimers containing fibrillin-1. J Biol Chem 275:2205–2210PubMedCrossRefGoogle Scholar
  116. Rifkin DB (2005) Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability. J Biol Chem 280:7409–7412PubMedCrossRefGoogle Scholar
  117. Ritty TM, Broekelmann T, Tisdale C, Milewicz DM, Mecham RP (1999) Processing of the fibrillin-1 carboxyl-terminal domain. J Biol Chem 274:8933–8940PubMedCrossRefGoogle Scholar
  118. Ritty TM, Broekelmann TJ, Werneck CC, Mecham RP (2003) Fibrillin-1 and -2 contain heparin-binding sites important for matrix deposition and that support cell attachment. Biochem J 375:425–432PubMedCrossRefGoogle Scholar
  119. Robinson P, Arteaga-Solis E, Baldock C, Collod-Beroud G, Booms P, De Paepe A, Dietz HC, Guo G, Handford PA, Judge DP, Kielty CM, Loeys B, Milewicz DM, Ney A, Ramirez F, Reinhardt DP, Tiedemann K, Whiteman P, Godfrey M (2006) The molecular genetics of Marfan syndrome and related disorders. J Med Genet 43:769–787PubMedCrossRefGoogle Scholar
  120. Rock MJ, Cain SA, Freeman LJ, Morgan A, Mellody K, Marson A, Shuttleworth CA, Weiss AS, Kielty CM (2004) Molecular basis of elastic fiber formation. Critical interactions and a tropoelastin-fibrillin-1 cross-link. J Biol Chem 279:23748–23758PubMedCrossRefGoogle Scholar
  121. Sabatier L, Chen D, Fagotto-Kaufmann C, Hubmacher D, McKee MD, Annis DS, Mosher DF, Reinhardt DP (2009) Fibrillin assembly requires fibronectin. Mol Biol Cell 20:846–858PubMedCrossRefGoogle Scholar
  122. Saharinen J, Keski-Oja J (2000) Specific sequence motif of 8-Cys repeats of TGF-beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-beta. Mol Biol Cell 11:2691–2704PubMedGoogle Scholar
  123. Saito S, Nishimura H, Brumeanu TD, Casares S, Stan AC, Honjo T, Bona CA (1999) Characterization of mutated protein encoded by partially duplicated fibrillin-1 gene in tight skin (TSK) mice. Mol Immunol 36:169–176PubMedCrossRefGoogle Scholar
  124. Sakai LY, Keene DR, Engvall E (1986) Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol 103:2499–2509PubMedCrossRefGoogle Scholar
  125. Sakai LY, Keene DR, Glanville RW, Bächinger HP (1991) Purification and partial characterization of fibrillin, a cysteine-rich structural component of connective tissue microfibrils. J Biol Chem 266:14763–14770PubMedGoogle Scholar
  126. Sakamoto H, Broekelmann T, Cheresh DA, Ramirez F, Rosenbloom J, Mecham RP (1996) Cell-type specific recognition of RGD- and non-RGD-containing cell binding domains in fibrillin-1. J Biol Chem 271:4916–4922PubMedCrossRefGoogle Scholar
  127. Segura AM, Luna RE, Horiba K, Stetler-Stevenson WG, McAllister HA Jr, Willerson JT, Ferrans VJ (1998) Immunohistochemistry of matrix metalloproteinases and their inhibitors in thoracic aortic aneurysms and aortic valves of patients with Marfan’s syndrome. Circulation 98:11331–11337Google Scholar
  128. Sengle G, Charbonneau NL, Ono RN, Sasaki T, Alvarez J, Keene DR, Bachinger HP, Sakai LY (2008a) Targeting of bone morphogenetic protein growth factor complexes to fibrillin. J Biol Chem 283:13874–13888PubMedCrossRefGoogle Scholar
  129. Sengle G, Ono RN, Lyons KM, Bachinger HP, Sakai LY (2008b) A new model for growth factor activation: type II receptors compete with the prodomain for BMP-7. J Mol Biol 381:1025–1039PubMedCrossRefGoogle Scholar
  130. Sherratt MJ, Baldock C, Haston JL, Holmes DF, Jones CJ, Shuttleworth CA, Wess TJ, Kielty CM (2003) Fibrillin microfibrils are stiff reinforcing fibres in compliant tissues. J Mol Biol 332:183–193PubMedCrossRefGoogle Scholar
  131. Sinha S, Heagerty AM, Shuttleworth CA, Kielty CM (2002) Expression of latent TGF-beta binding proteins and association with TGF-beta 1 and fibrillin-1 following arterial injury. Cardiovasc Res 53:971–983PubMedCrossRefGoogle Scholar
  132. Siracusa LD, McGrath R, Ma Q, Moskow JJ, Manne J, Christner PJ, Buchberg AM, Jimenez SA (1996) A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation. Genome Res 6:300–313PubMedCrossRefGoogle Scholar
  133. Skovby F, Kraus JP (2002) The homocystinurias. In: Royce PM, Steinmann B (eds) Connective tissue and its heritable disorders. Wiley-Liss, Inc., New York, pp 627–650CrossRefGoogle Scholar
  134. Taipale J, Miyazono K, Heldin CH, Keski-Oja J (1994) Latent transforming growth factor-β1 associates to fibroblast extracellular matrix via latent TGF-β binding protein. J Cell Biol 124:171–181PubMedCrossRefGoogle Scholar
  135. Taipale J, Saharinen J, Hedman K, Keski-Oja J (1996) Latent transforming growth factor-beta 1 and its binding protein are components of extracellular matrix microfibrils. J Histochem Cytochem 44:875–889PubMedGoogle Scholar
  136. ten Dijke P, Arthur HM (2007) Extracellular control of TGF-beta signalling in vascular development and disease. Nat Rev Mol Cell Biol 8:857–869PubMedCrossRefGoogle Scholar
  137. Thurmond FA, Trotter JA (1996) Morphology and biomechanics of the microfibrillar network of sea cucumber dermis. J Exp Biol 199:1817–1828PubMedGoogle Scholar
  138. Thurmond FA, Koob TJ, Bowness JM, Trotter JA (1997) Partial biochemical and immunologic characterization of fibrillin microfibrils from sea cucumber dermis. Connect Tissue Res 36:211–222PubMedCrossRefGoogle Scholar
  139. Tiedemann K, Bätge B, Müller PK, Reinhardt DP (2001) Interactions of fibrillin-1 with heparin/heparan sulfate: implications for microfibrillar assembly. J Biol Chem 276:36035–36042PubMedCrossRefGoogle Scholar
  140. Tiedemann K, Bätge B, Reinhardt DP (2004) Assembly of microfibrils. In: Robinson PN, Godfrey M (eds) Marfan syndrome: a primer for clinicians and scientists. Landes Bioscience, Georgetown, TX, USA, pp 130–142Google Scholar
  141. Tiedemann K, Sasaki T, Gustafsson E, Göhring W, Bätge B, Notbohm H, Timpl R, Wedel T, Schlötzer-Schrehardt U, Reinhardt DP (2005) Microfibrils at basement membrane zones interact with perlecan via fibrillin-1. J Biol Chem 280:11404–11412PubMedCrossRefGoogle Scholar
  142. Trask TM, Ritty TM, Broekelmann T, Tisdale C, Mecham RP (1999) N-terminal domains of fibrillin 1 and fibrillin 2 direct the formation of homodimers: a possible first step in microfibril assembly. Biochem J 340:693–701PubMedCrossRefGoogle Scholar
  143. Tsuji T (1986) Marfan syndrome: demonstration of abnormal elastic fibers in skin. J Cutan Pathol 13:144–153PubMedCrossRefGoogle Scholar
  144. Unsöld C, Hyytiäinen M, Bruckner-Tuderman L, Keski-Oja J (2001) Latent TGF-beta binding protein LTBP-1 contains three potential extracellular matrix interacting domains. J Cell Sci 114:187–197PubMedGoogle Scholar
  145. Viljoen D (1994) Congenital contractural arachnodactyly. J Med Genet 31:640–643PubMedCrossRefGoogle Scholar
  146. Wagenseil JE, Mecham RP (2007) New insights into elastic fiber assembly. Birth Defects Res C Embryo Today 81:229–240PubMedCrossRefGoogle Scholar
  147. Wallace RN, Streeten BW, Hanna RB (1991) Rotary shadowing of elastic system microfibrils in the ocular zonule, vitreous, and ligament nuchae. Curr Eye Res 10:99–109PubMedCrossRefGoogle Scholar
  148. Wallis DD, Putnam EA, Cretoiu JS, Carmical SG, Cao SN, Thomas G, Milewicz DM (2003) Profibrillin-1 maturation by human dermal fibroblasts: proteolytic processing and molecular chaperones. J Cell Biochem 90:641–652PubMedCrossRefGoogle Scholar
  149. Wang MC, Lu Y, Baldock C (2009) Fibrillin microfibrils: a key role for the interbead region in elasticity. J Mol Biol 388:168–179PubMedCrossRefGoogle Scholar
  150. Weinbaum JS, Broekelmann TJ, Pierce RA, Werneck CC, Segade F, Craft CS, Knutsen RH, Mecham RP (2008) Deficiency in microfibril-associated glycoprotein-1 leads to complex phenotypes in multiple organ systems. J Biol Chem 283:25533–25543PubMedCrossRefGoogle Scholar
  151. Werner JM, Knott V, Handford PA, Campbell ID, Downing AK (2000) Backbone dynamics of a cbEGF domain pair in the presence of calcium. J Mol Biol 296:1065–1078PubMedCrossRefGoogle Scholar
  152. Wess TJ, Purslow PP, Sherratt MJ, Ashworth J, Shuttleworth CA, Kielty CM (1998) Calcium determines the supramolecular organization of fibrillin-rich microfibrils. J Cell Biol 141:829–837PubMedCrossRefGoogle Scholar
  153. Whiteman P, Willis AC, Warner A, Brown J, Redfield C, Handford PA (2007) Cellular and molecular studies of Marfan syndrome mutations identify co-operative protein folding in the cbEGF12-13 region of fibrillin-1. Hum Mol Genet 16:907–918PubMedCrossRefGoogle Scholar
  154. Wipff PJ, Hinz B (2008) Integrins and the activation of latent transforming growth factor beta1 – an intimate relationship. Eur J Cell Biol 87:601–615PubMedCrossRefGoogle Scholar
  155. Wright DW, Mayne R (1988) Vitreous humor of chicken contains two fibrillar systems: an analysis of their structure. J Ultrastruct Mol Struct Res 100:224–234PubMedCrossRefGoogle Scholar
  156. Yin W, Smiley E, Germiller J, Sanguineti C, Lawton T, Pereira L, Ramirez F, Bonadio J (1995) Primary structure and developmental expression of Fbn-1, the mouse fibrillin gene. J Biol Chem 270:1798–1806PubMedCrossRefGoogle Scholar
  157. Zacchigna L, Vecchione C, Notte A, Cordenonsi M, Dupont S, Maretto S, Cifelli G, Ferrari A, Maffei A, Fabbro C, Braghetta P, Marino G, Selvetella G, Aretini A, Colonnese C, Bettarini U, Russo G, Soligo S, Adorno M, Bonaldo P, Volpin D, Piccolo S, Lembo G, Bressan GM (2006) Emilin1 links TGF-beta maturation to blood pressure homeostasis. Cell 124:929–942PubMedCrossRefGoogle Scholar
  158. Zhang H, Apfelroth SD, Hu W, Davis EC, Sanguineti C, Bonadio J, Mecham RP, Ramirez F (1994) Structure and expression of fibrillin-2, a novel microfibrillar component preferentially located in elastic matrices. J Cell Biol 124:855–863PubMedCrossRefGoogle Scholar
  159. Zhang H, Hu W, Ramirez F (1995) Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J Cell Biol 129:1165–1176PubMedCrossRefGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Department of Anatomy and Cell Biology, Faculty of MedicineMcGill University MontrealMontrealCanada

Personalised recommendations