PDBsum entry 2bap

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protein Protein-protein interface(s) links
Signaling protein PDB id
Protein chains
294 a.a. *
16 a.a. *
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Crystal structure of the n-terminal mdia1 armadillo repeat region and dimerisation domain in complex with the mdia1 autoregulatory domain (dad)
Structure: Diaphanous protein homolog 1. Chain: b, a. Fragment: mdia1 n-terminal regulatory domain. Synonym: diaphanous-related formin 1, drf1, mdia1, p140mdia. Engineered: yes. Diaphanous protein homolog 1. Chain: d, c. Fragment: mdia1 autoregulatory domain, dad.
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: diaph1, diap1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Tetramer (from PDB file)
3.30Å     R-factor:   0.292     R-free:   0.364
Authors: M.Lammers,R.Rose,A.Scrima,A.Wittinghofer
Key ref:
M.Lammers et al. (2005). The regulation of mDia1 by autoinhibition and its release by Rho*GTP. EMBO J, 24, 4176-4187. PubMed id: 16292343 DOI: 10.1038/sj.emboj.7600879
14-Oct-05     Release date:   07-Mar-06    
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Protein chains
Pfam   ArchSchema ?
O08808  (DIAP1_MOUSE) -  Protein diaphanous homolog 1
1255 a.a.
294 a.a.
Protein chains
Pfam   ArchSchema ?
O08808  (DIAP1_MOUSE) -  Protein diaphanous homolog 1
1255 a.a.
16 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     cellular component organization   4 terms 
  Biochemical function     actin binding     2 terms  


DOI no: 10.1038/sj.emboj.7600879 EMBO J 24:4176-4187 (2005)
PubMed id: 16292343  
The regulation of mDia1 by autoinhibition and its release by Rho*GTP.
M.Lammers, R.Rose, A.Scrima, A.Wittinghofer.
Formins induce the nucleation and polymerisation of unbranched actin filaments via the formin-homology domains 1 and 2. Diaphanous-related formins (Drfs) are regulated by a RhoGTPase-binding domain situated in the amino-terminal (N-terminal) region and a carboxy-terminal Diaphanous-autoregulatory domain (DAD), whose interaction stabilises an autoinhibited inactive conformation. Binding of active Rho releases DAD and activates the catalytic activity of mDia. Here, we report on the interaction of DAD with the regulatory N-terminus of mDia1 (mDia(N)) and its release by Rho*GTP. We have defined the elements required for tight binding and solved the three-dimensional structure of a complex between an mDia(N) construct and DAD by X-ray crystallography. The core DAD region is an alpha-helical peptide, which binds in the most highly conserved region of mDia(N) using mainly hydrophobic interactions. The structure suggests a two-step mechanism for release of autoinhibition whereby Rho*GTP, although having a partially nonoverlapping binding site, displaces DAD by ionic repulsion and steric clashes. We show that Rho*GTP accelerates the dissociation of DAD from the mDia(N)*DAD complex.
  Selected figure(s)  
Figure 5.
Figure 5 Structural model for release of DAD by Rho binding. (A) Model of a complex of mDia[N] with Rho GTP and the DCR, using the previous RhoC complex structure (Rose et al, 2005b) and the DAD complex structure obtained here and the superimposition shown in Figure 4B. (B) Details of the electrostatic repulsion between DAD and Rho in a proposed ternary mDia[N]-Rho-DAD complex; the steric clash on inserting the next DAD residue, Thr1179, is indicated by a green circle.
Figure 7.
Figure 7 Schematic two-step-binding model of DAD release from the regulatory region of mDia1 by Rho GTP, as described in the text.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO J (2005, 24, 4176-4187) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21119010 R.Gorelik, C.Yang, V.Kameswaran, R.Dominguez, and T.Svitkina (2011).
Mechanisms of plasma membrane targeting of formin mDia2 through its amino terminal domains.
  Mol Biol Cell, 22, 189-201.  
  20927338 A.Nezami, F.Poy, A.Toms, W.Zheng, and M.J.Eck (2010).
Crystal structure of a complex between amino and carboxy terminal fragments of mDia1: insights into autoinhibition of diaphanous-related formins.
  PLoS One, 5, 0.
PDB code: 3o4x
20008558 A.Sakane, K.Honda, and T.Sasaki (2010).
Rab13 regulates neurite outgrowth in PC12 cells through its effector protein, JRAB/MICAL-L2.
  Mol Cell Biol, 30, 1077-1087.  
20023659 E.J.Brown, J.S.Schlöndorff, D.J.Becker, H.Tsukaguchi, A.L.Uscinski, H.N.Higgs, J.M.Henderson, and M.R.Pollak (2010).
Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis.
  Nat Genet, 42, 72-76.  
20237478 K.G.Campellone, and M.D.Welch (2010).
A nucleator arms race: cellular control of actin assembly.
  Nat Rev Mol Cell Biol, 11, 237-251.  
21035343 M.Patel, Y.Margaron, N.Fradet, Q.Yang, B.Wilkes, M.Bouvier, K.Hofmann, and J.F.Côté (2010).
An evolutionarily conserved autoinhibitory molecular switch in ELMO proteins regulates Rac signaling.
  Curr Biol, 20, 2021-2027.  
20177055 S.Barkó, B.Bugyi, M.F.Carlier, R.Gombos, T.Matusek, J.Mihály, and M.Nyitrai (2010).
Characterization of the biochemical properties and biological function of the formin homology domains of Drosophila DAAM.
  J Biol Chem, 285, 13154-13169.  
  20927366 S.F.Ang, Z.S.Zhao, L.Lim, and E.Manser (2010).
DAAM1 is a formin required for centrosome re-orientation during cell migration.
  PLoS One, 5, 0.  
20660154 S.Watanabe, K.Okawa, T.Miki, S.Sakamoto, T.Morinaga, K.Segawa, T.Arakawa, M.Kinoshita, T.Ishizaki, and S.Narumiya (2010).
Rho and anillin-dependent control of mDia2 localization and function in cytokinesis.
  Mol Biol Cell, 21, 3193-3204.  
  20927343 T.Otomo, D.R.Tomchick, C.Otomo, M.Machius, and M.K.Rosen (2010).
Crystal structure of the Formin mDia1 in autoinhibited conformation.
  PLoS One, 5, 0.
PDB code: 3obv
19366733 E.S.Chhabra, V.Ramabhadran, S.A.Gerber, and H.N.Higgs (2009).
INF2 is an endoplasmic reticulum-associated formin protein.
  J Cell Sci, 122, 1430-1440.  
19909364 J.Zhang, B.Dong, and K.A.Siminovitch (2009).
Contributions of Wiskott-Aldrich syndrome family cytoskeletal regulatory adapters to immune regulation.
  Immunol Rev, 232, 175-194.  
19365405 S.L.Lai, A.J.Chien, and R.T.Moon (2009).
Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis.
  Cell Res, 19, 532-545.  
18786395 A.Schulte, B.Stolp, A.Schönichen, O.Pylypenko, A.Rak, O.T.Fackler, and M.Geyer (2008).
The human formin FHOD1 contains a bipartite structure of FH3 and GTPase-binding domains required for activation.
  Structure, 16, 1313-1323.
PDB code: 3dad
18922799 B.I.Hudson, A.Z.Kalea, M.Del Mar Arriero, E.Harja, E.Boulanger, V.D'Agati, and A.M.Schmidt (2008).
Interaction of the RAGE Cytoplasmic Domain with Diaphanous-1 Is Required for Ligand-stimulated Cellular Migration through Activation of Rac1 and Cdc42.
  J Biol Chem, 283, 34457-34468.  
18786389 C.Baarlink, and R.Grosse (2008).
A GBD uncovered: the FHOD1 N terminus is formin'.
  Structure, 16, 1287-1288.  
18388856 C.X.Bai, S.Kim, W.P.Li, A.J.Streets, A.C.Ong, and L.Tsiokas (2008).
Activation of TRPP2 through mDia1-dependent voltage gating.
  EMBO J, 27, 1345-1356.  
  18212360 D.D.Tang, and Y.Anfinogenova (2008).
Physiologic properties and regulation of the actin cytoskeleton in vascular smooth muscle.
  J Cardiovasc Pharmacol Ther, 13, 130-140.  
18829452 M.Lammers, S.Meyer, D.Kühlmann, and A.Wittinghofer (2008).
Specificity of Interactions between mDia Isoforms and Rho Proteins.
  J Biol Chem, 283, 35236-35246.
PDB code: 3eg5
18239683 R.Takeya, K.Taniguchi, S.Narumiya, and H.Sumimoto (2008).
The mammalian formin FHOD1 is activated through phosphorylation by ROCK and mediates thrombin-induced stress fibre formation in endothelial cells.
  EMBO J, 27, 618-628.  
18694941 S.Hannemann, R.Madrid, J.Stastna, T.Kitzing, J.Gasteier, A.Schönichen, J.Bouchet, A.Jimenez, M.Geyer, R.Grosse, S.Benichou, and O.T.Fackler (2008).
The Diaphanous-related Formin FHOD1 associates with ROCK1 and promotes Src-dependent plasma membrane blebbing.
  J Biol Chem, 283, 27891-27903.  
18941507 S.L.Lai, T.H.Chan, M.J.Lin, W.P.Huang, S.W.Lou, and S.J.Lee (2008).
Diaphanous-related formin 2 and profilin I are required for gastrulation cell movements.
  PLoS ONE, 3, e3439.  
18347041 S.Majumder, and A.Lohia (2008).
Entamoeba histolytica encodes unique formins, a subset of which regulates DNA content and cell division.
  Infect Immun, 76, 2368-2378.  
18218625 T.Higashi, T.Ikeda, R.Shirakawa, H.Kondo, M.Kawato, M.Horiguchi, T.Okuda, K.Okawa, S.Fukai, O.Nureki, T.Kita, and H.Horiuchi (2008).
Biochemical characterization of the Rho GTPase-regulated actin assembly by diaphanous-related formins, mDia1 and Daam1, in platelets.
  J Biol Chem, 283, 8746-8755.  
  17909294 A.Schulte, A.Rak, O.Pylypenko, D.Ludwig, and M.Geyer (2007).
Purification, crystallization and preliminary structural characterization of the N-terminal region of the human formin-homology protein FHOD1.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 878-881.  
17373907 B.L.Goode, and M.J.Eck (2007).
Mechanism and function of formins in the control of actin assembly.
  Annu Rev Biochem, 76, 593-627.  
17620407 D.T.Brandt, S.Marion, G.Griffiths, T.Watanabe, K.Kaibuchi, and R.Grosse (2007).
Dia1 and IQGAP1 interact in cell migration and phagocytic cup formation.
  J Cell Biol, 178, 193-200.  
17482208 J.Lu, W.Meng, F.Poy, S.Maiti, B.L.Goode, and M.J.Eck (2007).
Structure of the FH2 domain of Daam1: implications for formin regulation of actin assembly.
  J Mol Biol, 369, 1258-1269.
PDB code: 2j1d
17986009 M.Yamashita, T.Higashi, S.Suetsugu, Y.Sato, T.Ikeda, R.Shirakawa, T.Kita, T.Takenawa, H.Horiuchi, S.Fukai, and O.Nureki (2007).
Crystal structure of human DAAM1 formin homology 2 domain.
  Genes Cells, 12, 1255-1265.
PDB code: 2z6e
17699595 S.G.Martin, S.A.Rincón, R.Basu, P.Pérez, and F.Chang (2007).
Regulation of the formin for3p by cdc42p and bud6p.
  Mol Biol Cell, 18, 4155-4167.  
17575049 T.M.Kitzing, A.S.Sahadevan, D.T.Brandt, H.Knieling, S.Hannemann, O.T.Fackler, J.Grosshans, and R.Grosse (2007).
Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion.
  Genes Dev, 21, 1478-1483.  
16943183 A.Seth, C.Otomo, and M.K.Rosen (2006).
Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1.
  J Cell Biol, 174, 701-713.  
16818491 E.S.Chhabra, and H.N.Higgs (2006).
INF2 Is a WASP homology 2 motif-containing formin that severs actin filaments and accelerates both polymerization and depolymerization.
  J Biol Chem, 281, 26754-26767.  
16829561 G.Papp, B.Bugyi, Z.Ujfalusi, S.Barkó, G.Hild, B.Somogyi, and M.Nyitrai (2006).
Conformational changes in actin filaments induced by formin binding to the barbed end.
  Biophys J, 91, 2564-2572.  
16959963 J.B.Moseley, and B.L.Goode (2006).
The yeast actin cytoskeleton: from cellular function to biochemical mechanism.
  Microbiol Mol Biol Rev, 70, 605-645.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.