title: Structure of three tandem filamin domains reveals auto-inhibition of ligand binding.
abstract: Human filamins are large actin-crosslinking proteins composed of an N-terminal actin-binding domain followed by 24 Ig-like domains (IgFLNs), which interact with numerous transmembrane receptors and cytosolic signaling proteins. Here we report the 2.5 A resolution structure of a three-domain fragment of human filamin A (IgFLNa19-21). The structure reveals an unexpected domain arrangement, with IgFLNa20 partially unfolded bringing IgFLNa21 into close proximity to IgFLNa19. Notably the N-terminus of IgFLNa20 forms a beta-strand that associates with the CD face of IgFLNa21 and occupies the binding site for integrin adhesion receptors. Disruption of this IgFLNa20-IgFLNa21 interaction enhances filamin binding to integrin beta-tails. Structural and functional analysis of other IgFLN domains suggests that auto-inhibition by adjacent IgFLN domains may be a general mechanism controlling filamin-ligand interactions. This can explain the increased integrin binding of filamin splice variants and provides a mechanism by which ligand binding might impact filamin structure.
authors: Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Yatish
authors: Y
authors: Lad
authors: Tiila
authors: T
authors: Kiema
authors: Pengju
authors: P
authors: Jiang
authors: Olli T
authors: OT
authors: Pentikäinen
authors: Charlotte H
authors: CH
authors: Coles
authors: Iain D
authors: ID
authors: Campbell
authors: David A
authors: DA
authors: Calderwood
authors: Jari
authors: J
authors: Ylänne
mesh_terms: D003285:Contractile Proteins / Q000737:chemistry* / Q000378:metabolism; D064448:Filamins; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D008840:Microfilament Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D016023:Integrins; D008024:Ligands; D008840:Microfilament Proteins
references: FEBS Lett. 2001 Jun 1;498(1):72-5
references: 11389901
references: Nat Rev Mol Cell Biol. 2001 Feb;2(2):138-45
references: 11252955
references: J Biomol NMR. 1995 Sep;6(2):135-40
references: 8589602
references: Biochim Biophys Acta. 2001 Apr 23;1538(2-3):99-117
references: 11336782
references: J Biomol NMR. 1998 May;11(4):451-6
references: 9691286
references: J Mol Biol. 1981 Jan 25;145(3):563-81
references: 6894945
references: Structure. 2005 Jan;13(1):111-9
references: 15642266
references: Cell. 1996 Jan 12;84(1):155-64
references: 8548820
references: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3919-24
references: 17360453
references: J Biomol NMR. 1995 Nov;6(3):277-93
references: 8520220
references: Neuron. 1998 Dec;21(6):1315-25
references: 9883725
references: Mol Cell Biol. 2004 Apr;24(7):3025-35
references: 15024089
references: Nat Cell Biol. 2001 Dec;3(12):1060-8
references: 11781567
references: Nat Struct Biol. 1999 Sep;6(9):836-41
references: 10467095
references: Nat Cell Biol. 2004 Nov;6(11):1034-8
references: 15516996
references: Mol Cell Biol. 2006 Sep;26(17):6522-34
references: 16914736
references: Structure. 2003 Mar;11(3):243-51
references: 12623012
references: Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19836-41
references: 17172441
references: J Muscle Res Cell Motil. 2005;26(6-8):355-65
references: 16341830
references: Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11764-8
references: 1465395
references: Hum Mol Genet. 2006 Aug 15;15(16):2457-67
references: 16825286
references: J Cell Biol. 1980 Dec;87(3 Pt 1):841-8
references: 6893990
references: J Cell Biol. 1990 Sep;111(3):1089-105
references: 2391361
references: Arch Biochem Biophys. 2000 May 1;377(1):80-4
references: 10775444
references: Acta Crystallogr D Biol Crystallogr. 2004 Mar;60(Pt 3):432-8
references: 14993666
references: Nat Genet. 2004 Apr;36(4):405-10
references: 14991055
references: Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
references: 2025413
references: J Biomol NMR. 1994 Mar;4(2):301-6
references: 8019138
references: Nat Struct Mol Biol. 2004 Jan;11(1):81-5
references: 14718927
references: Biochemistry. 2001 May 29;40(21):6275-83
references: 11371189
references: Trends Biochem Sci. 2006 Jul;31(7):411-9
references: 16781869
references: Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
references: 15299926
references: Biochemistry. 2006 Jun 27;45(25):7778-86
references: 16784229
references: Mol Cell. 2006 Feb 3;21(3):337-47
references: 16455489
references: Nat Struct Biol. 1997 Mar;4(3):223-30
references: 9164464
references: Cell. 2002 Sep 20;110(6):673-87
references: 12297042
references: J Cell Biol. 2002 Jan 21;156(2):361-76
references: 11807098
references: J Biol Chem. 1998 Jan 16;273(3):1689-98
references: 9430714
references: Blood. 1998 Aug 15;92(4):1268-76
references: 9694715
references: J Cell Biol. 1980 May;85(2):489-95
references: 6768755
references: EMBO J. 2001 Apr 2;20(7):1519-29
references: 11285216
references: Blood. 2006 Mar 1;107(5):1925-32
references: 16293600
references: FEBS Lett. 2004 Jul 2;569(1-3):185-90
references: 15225631
references: J Biol Chem. 1998 Mar 13;273(11):6104-9
references: 9497328
references: J Biol Chem. 2002 Dec 6;277(49):47541-50
references: 12324467
references: J Muscle Res Cell Motil. 1981 Jun;2(2):193-202
references: 6894930
references: Am J Hum Genet. 2005 Aug;77(2):297-304
references: 15929027
references: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references: 15572765
references: Circulation. 2007 Jan 2;115(1):40-9
references: 17190868
references: Biochem Biophys Res Commun. 1998 Oct 29;251(3):914-9
references: 9791010
references: Nat Cell Biol. 2006 Aug;8(8):803-14
references: 16862148
references: Nat Genet. 2003 Apr;33(4):487-91
references: 12612583
references: J Mol Biol. 2004 Oct 1;342(5):1637-46
references: 15364587
references: Nat Cell Biol. 2002 Sep;4(9):681-90
references: 12198493