title: Structure of the fibrillin-1 N-terminal domains suggests that heparan sulfate regulates the early stages of microfibril assembly.
abstract: The human extracellular matrix glycoprotein fibrillin-1 is the primary component of the 10- to 12-nm-diameter microfibrils, which perform key structural and regulatory roles in connective tissues. Relatively little is known about the molecular mechanisms of fibrillin assembly into microfibrils. Studies using recombinant fibrillin fragments indicate that an interaction between the N- and C-terminal regions drives head-to-tail assembly. Here, we present the structure of a fibrillin N-terminal fragment comprising the fibrillin unique N-terminal (FUN) and the first three epidermal growth factor (EGF)-like domains (FUN-EGF3). Two rod-like domain pairs are separated by a short, flexible linker between the EGF1 and EGF2 domains. We also show that the binding site for the C-terminal region spans multiple domains and overlaps with a heparin interaction site. These data suggest that heparan sulfate may sequester fibrillin at the cell surface via FUN-EGF3 prior to aggregation of the C terminus, thereby regulating microfibril assembly.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Yadin
authors.forename: Ian B
authors.initials: IB
authors.lastname: Robertson
authors.forename: Joanne
authors.initials: J
authors.lastname: McNaught-Davis
authors.forename: Paul
authors.initials: P
authors.lastname: Evans
authors.forename: David
authors.initials: D
authors.lastname: Stoddart
authors.forename: Penny A
authors.initials: PA
authors.lastname: Handford
authors.forename: Sacha A
authors.initials: SA
authors.lastname: Jensen
authors.forename: Christina
authors.initials: C
authors.lastname: Redfield
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D000071838:Fibrillin-1; D000071837:Fibrillins; D006497:Heparan Sulfate / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D020894:Microfibrils / Q000737:chemistry*; D008840:Microfilament Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D006497:Heparan Sulfate; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines
references.citation: Biochemistry. 2009 May 19;48(19):4031-9
references.pmid: 19309110
references.citation: Hum Mol Genet. 1998 Dec;7(13):2039-44
references.pmid: 9817919
references.citation: Int J Biochem Cell Biol. 2000 Feb;32(2):201-14
references.pmid: 10687954
references.citation: J Biol Chem. 2007 Mar 23;282(12):8935-46
references.pmid: 17255108
references.citation: Nat Struct Mol Biol. 2008 Aug;15(8):849-57
references.pmid: 18660822
references.citation: J Biol Chem. 2005 Aug 26;280(34):30526-37
references.pmid: 15980072
references.citation: Int J Biochem Cell Biol. 2010 Jul;42(7):1084-93
references.pmid: 20236620
references.citation: Biochemistry. 1989 Nov 14;28(23):8972-9
references.pmid: 2690953
references.citation: J Biol Chem. 2001 Sep 21;276(38):36035-42
references.pmid: 11461921
references.citation: J Biol Chem. 2008 May 16;283(20):13874-88
references.pmid: 18339631
references.citation: FEBS Lett. 1996 Apr 22;384(3):247-50
references.pmid: 8617364
references.citation: J Mol Biol. 2002 Feb 8;316(1):113-25
references.pmid: 11829507
references.citation: PLoS One. 2012;7(3):e33560
references.pmid: 22438950
references.citation: Biomol NMR Assign. 2014 Apr;8(1):75-80
references.pmid: 23264024
references.citation: J Biol Chem. 2002 Dec 27;277(52):50795-804
references.pmid: 12399449
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W545-9
references.pmid: 20457744
references.citation: J Mol Biol. 1996 Apr 26;258(1):104-16
references.pmid: 8613981
references.citation: J Biol Chem. 1991 Aug 5;266(22):14763-70
references.pmid: 1860873
references.citation: J Cell Sci. 1991 Aug;99 ( Pt 4):797-807
references.pmid: 1770007
references.citation: EMBO J. 1997 Nov 17;16(22):6659-66
references.pmid: 9362480
references.citation: Nat Struct Mol Biol. 2011 Jul 10;18(8):886-93
references.pmid: 21743455
references.citation: Cell. 1996 May 17;85(4):597-605
references.pmid: 8653794
references.citation: J Biol Chem. 2009 Jun 19;284(25):16872-16881
references.pmid: 19349279
references.citation: J Biol Chem. 2000 Jan 21;275(3):2205-10
references.pmid: 10636927
references.citation: Am J Med Genet A. 2009 Jul;149A(7):1452-9
references.pmid: 19533785
references.citation: Q Rev Biophys. 1996 May;29(2):119-67
references.pmid: 8870072
references.citation: J Biol Chem. 2011 Feb 18;286(7):5087-99
references.pmid: 21135108
references.citation: J Biomol NMR. 2009 Aug;44(4):213-23
references.pmid: 19548092
references.citation: J Histochem Cytochem. 1991 Apr;39(4):441-9
references.pmid: 2005373
references.citation: Hum Mol Genet. 1993 Jul;2(7):961-8
references.pmid: 8364578
references.citation: J Biol Chem. 2005 Apr 8;280(14):14076-84
references.pmid: 15649891
references.citation: Biochem J. 2011 Jan 15;433(2):263-76
references.pmid: 21175431
references.citation: Am J Hum Genet. 2011 Jul 15;89(1):7-14
references.pmid: 21683322
references.citation: J Am Chem Soc. 2004 Jun 16;126(23):7281-92
references.pmid: 15186165
references.citation: Eur J Hum Genet. 2009 Sep;17(9):1121-8
references.pmid: 19293843
references.citation: Biomol NMR Assign. 2014 Apr;8(1):189-94
references.pmid: 23649688
references.citation: Sci Transl Med. 2010 Mar 17;2(23):23ra20
references.pmid: 20375004
references.citation: J Mol Biol. 1996 Jan 12;255(1):22-7
references.pmid: 8568869
references.citation: J Cell Biol. 1986 Dec;103(6 Pt 1):2499-509
references.pmid: 3536967
references.citation: Hum Mol Genet. 2007 Apr 15;16(8):907-18
references.pmid: 17324963
references.citation: J Biol Chem. 2008 Apr 25;283(17):11785-93
references.pmid: 18296446
references.citation: Dev Biol. 1995 Jun;169(2):662-72
references.pmid: 7781906
references.citation: J Med Genet. 2003 Jan;40(1):34-6
references.pmid: 12525539
references.citation: Protein Sci. 1996 Jun;5(6):1067-80
references.pmid: 8762138
references.citation: Proc Natl Acad Sci U S A. 2008 May 6;105(18):6548-53
references.pmid: 18448684
references.citation: Nat Struct Mol Biol. 2009 Jul;16(7):698-703
references.pmid: 19561611
references.citation: J Biomol NMR. 1996 Dec;8(4):477-86
references.pmid: 9008363
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):11922-7
references.pmid: 16880403
references.citation: Hepatology. 2006 Mar;43(3):415-24
references.pmid: 16496348
references.citation: Structure. 2009 May 13;17(5):759-68
references.pmid: 19446531
references.citation: Nature. 1991 Jul 25;352(6333):330-4
references.pmid: 1852206
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W590-4
references.pmid: 15215457
references.citation: J Biol Chem. 2005 Feb 11;280(6):5013-21
references.pmid: 15569675
references.citation: Am J Med Genet A. 2006 Aug 15;140(16):1719-25
references.pmid: 16835936
references.citation: Structure. 2004 Apr;12(4):717-29
references.pmid: 15062093
references.citation: J Biol Chem. 2007 Feb 9;282(6):4007-20
references.pmid: 17158461