PDBsum entry 2a3z

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protein ligands metals Protein-protein interface(s) links
Structural protein PDB id
Protein chains
361 a.a.
260 a.a. *
17 a.a. *
GOL ×3
_CA ×2
Waters ×395
* Residue conservation analysis
PDB id:
Name: Structural protein
Title: Ternary complex of the wh2 domain of wasp with actin-dnase i
Structure: Actin, alpha skeletal muscle. Chain: a. Synonym: alpha-actin 1. Deoxyribonuclease-1. Chain: b. Synonym: deoxyribonuclease i, dnase i. Wiskott-aldrich syndrome protein. Chain: c. Fragment: wh2 domain, residues 430-458.
Source: Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986. Other_details: skeletal muscle. Bos taurus. Cattle. Organism_taxid: 9913. Other_details: pancreas. Synthetic: yes.
Biol. unit: Trimer (from PQS)
2.08Å     R-factor:   0.159     R-free:   0.210
Authors: D.Chereau,F.Kerff,R.Dominguez
Key ref:
D.Chereau et al. (2005). Actin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly. Proc Natl Acad Sci U S A, 102, 16644-16649. PubMed id: 16275905 DOI: 10.1073/pnas.0507021102
27-Jun-05     Release date:   01-Nov-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P68135  (ACTS_RABIT) -  Actin, alpha skeletal muscle
377 a.a.
361 a.a.*
Protein chain
Pfam   ArchSchema ?
P00639  (DNAS1_BOVIN) -  Deoxyribonuclease-1
282 a.a.
260 a.a.
Protein chain
Pfam   ArchSchema ?
P42768  (WASP_HUMAN) -  Wiskott-Aldrich syndrome protein
502 a.a.
17 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   8 terms 
  Biological process     apoptotic process   5 terms 
  Biochemical function     nucleotide binding     13 terms  


DOI no: 10.1073/pnas.0507021102 Proc Natl Acad Sci U S A 102:16644-16649 (2005)
PubMed id: 16275905  
Actin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly.
D.Chereau, F.Kerff, P.Graceffa, Z.Grabarek, K.Langsetmo, R.Dominguez.
Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 (WH2) is a small and widespread actin-binding motif. In the WASP family, WH2 plays a role in filament nucleation by Arp2/3 complex. Here we describe the crystal structures of complexes of actin with the WH2 domains of WASP, WASP-family verprolin homologous protein, and WASP-interacting protein. Despite low sequence identity, WH2 shares structural similarity with the N-terminal portion of the actin monomer-sequestering thymosin beta domain (Tbeta). We show that both domains inhibit nucleotide exchange by targeting the cleft between actin subdomains 1 and 3, a common binding site for many unrelated actin-binding proteins. Importantly, WH2 is significantly shorter than Tbeta but binds actin with approximately 10-fold higher affinity. WH2 lacks a C-terminal extension that in Tbeta4 becomes involved in monomer sequestration by interfering with intersubunit contacts in F-actin. Owing to their shorter length, WH2 domains connected in tandem by short linkers can coexist with intersubunit contacts in F-actin and are proposed to function in filament nucleation by lining up actin subunits along a filament strand. The WH2-central region of WASP-family proteins is proposed to function in an analogous way by forming a special class of tandem repeats whose function is to line up actin and Arp2 during Arp2/3 nucleation. The structures also suggest a mechanism for how profilin-binding Pro-rich sequences positioned N-terminal to WH2 could feed actin monomers directly to WH2, thereby playing a role in filament elongation.
  Selected figure(s)  
Figure 2.
Fig. 2. WH2-actin structures. (A-C) Structures of the WH2 domains of WASP, WAVE2, and WIP determined as ternary complexes with actin (gray) and DNase I (see Fig. 5). (D) Superimposition of the structures of ciboulot (9) and T 4 (10), which together represent T -actin. (E-G) Close-view comparisons of different parts of the WH2-actin and T -actin structures shown in A-D. (H) Partial overlap between the actin-binding sites of profilin (blue) and WH2.
Figure 4.
Fig. 4. Structural basis for the role of WH2 in filament nucleation and elongation. (A) In most proteins WH2 occurs in the form of tandem repeats C-terminal to Pro-rich sequences that support the binding of profilin-actin. The structures of WH2-actin suggest that this basic arrangement may allow WH2 to function in filament nucleation and elongation, two processes that are tightly connected but that can be conceptually separated. (B) Tandem repeats of short WH2 domains connected by short linkers can function to line up actin monomers along a filament strand, thereby playing a role in filament nucleation. Given the existing similarity between the C region of WASP/WAVE and WH2 (see Fig. 1B), the WH2 C region (C) may represent a specialized form of tandem repeat whose role is to add an actin subunit at the barbed end of Arp2 during Arp2/3 nucleation. (C) A superimposition of the structures of profilin-actin (19) and profilin-polyPro (36) with the structures of WH2-actin illustrates how profilin bound to the last consensus profilin-binding site (27) could deliver its actin directly to WH2, playing a role in filament elongation. A partial overlap between the actin-binding sites of profilin and WH2 may then help release profilin from the barbed end of the growing filament. Such a mechanism may constitute the basis for the so-called actoclampin model of actin polymerization (35).
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23222643 M.E.Thompson, E.G.Heimsath, T.J.Gauvin, H.N.Higgs, and F.J.Kull (2013).
FMNL3 FH2-actin structure gives insight into formin-mediated actin nucleation and elongation.
  Nat Struct Mol Biol, 20, 111-118.
PDB code: 4eah
21873984 B.Yu, H.C.Cheng, C.A.Brautigam, D.R.Tomchick, and M.K.Rosen (2011).
Mechanism of actin filament nucleation by the bacterial effector VopL.
  Nat Struct Mol Biol, 18, 1068-1074.
PDB code: 3seo
21217643 D.Breitsprecher, A.K.Kiesewetter, J.Linkner, M.Vinzenz, T.E.Stradal, J.V.Small, U.Curth, R.B.Dickinson, and J.Faix (2011).
Molecular mechanism of Ena/VASP-mediated actin-filament elongation.
  EMBO J, 30, 456-467.  
21873985 S.Namgoong, M.Boczkowska, M.J.Glista, J.D.Winkelman, G.Rebowski, D.R.Kovar, and R.Dominguez (2011).
Mechanism of actin filament nucleation by Vibrio VopL and implications for tandem W domain nucleation.
  Nat Struct Mol Biol, 18, 1060-1067.
PDB code: 3ryl
21315084 T.Ito, A.Narita, T.Hirayama, M.Taki, S.Iyoshi, Y.Yamamoto, Y.Maéda, and T.Oda (2011).
Human spire interacts with the barbed end of the actin filament.
  J Mol Biol, 408, 18-25.  
20538977 A.M.Ducka, P.Joel, G.M.Popowicz, K.M.Trybus, M.Schleicher, A.A.Noegel, R.Huber, T.A.Holak, and T.Sitar (2010).
Structures of actin-bound Wiskott-Aldrich syndrome protein homology 2 (WH2) domains of Spire and the implication for filament nucleation.
  Proc Natl Acad Sci U S A, 107, 11757-11762.
PDB codes: 3mmv 3mn5 3mn6 3mn7 3mn9
20536449 C.Husson, F.X.Cantrelle, P.Roblin, D.Didry, K.H.Le, J.Perez, E.Guittet, C.Van Heijenoort, L.Renault, and M.F.Carlier (2010).
Multifunctionality of the beta-thymosin/WH2 module: G-actin sequestration, actin filament growth, nucleation, and severing.
  Ann N Y Acad Sci, 1194, 44-52.  
20037163 D.Delaroche, F.X.Cantrelle, F.Subra, C.Van Heijenoort, E.Guittet, C.Y.Jiao, L.Blanchoin, G.Chassaing, S.Lavielle, C.Auclair, and S.Sagan (2010).
Cell-penetrating peptides with intracellular actin-remodeling activity in malignant fibroblasts.
  J Biol Chem, 285, 7712-7721.  
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.  
21124947 M.Guéroult, D.Picot, J.Abi-Ghanem, B.Hartmann, and M.Baaden (2010).
How cations can assist DNase I in DNA binding and hydrolysis.
  PLoS Comput Biol, 6, e1001000.  
20532239 M.Hertzog, F.Milanesi, L.Hazelwood, A.Disanza, H.Liu, E.Perlade, M.G.Malabarba, S.Pasqualato, A.Maiolica, S.Confalonieri, C.Le Clainche, N.Offenhauser, J.Block, K.Rottner, P.P.Di Fiore, M.F.Carlier, N.Volkmann, D.Hanein, and G.Scita (2010).
Molecular basis for the dual function of Eps8 on actin dynamics: bundling and capping.
  PLoS Biol, 8, e1000387.  
20075609 N.Watanabe (2010).
Inside view of cell locomotion through single-molecule: fast F-/G-actin cycle and G-actin regulation of polymer restoration.
  Proc Jpn Acad Ser B Phys Biol Sci, 86, 62-83.  
20533885 S.B.Padrick, and M.K.Rosen (2010).
Physical mechanisms of signal integration by WASP family proteins.
  Annu Rev Biochem, 79, 707-735.  
20446344 S.H.Lee, and R.Dominguez (2010).
Regulation of actin cytoskeleton dynamics in cells.
  Mol Cells, 29, 311-325.  
21107423 Z.Chen, D.Borek, S.B.Padrick, T.S.Gomez, Z.Metlagel, A.M.Ismail, J.Umetani, D.D.Billadeau, Z.Otwinowski, and M.K.Rosen (2010).
Structure and control of the actin regulatory WAVE complex.
  Nature, 468, 533-538.
PDB code: 3p8c
19406642 B.Qualmann, and M.M.Kessels (2009).
New players in actin polymerization--WH2-domain-containing actin nucleators.
  Trends Cell Biol, 19, 276-285.  
19217847 D.Van Valen, M.Haataja, and R.Phillips (2009).
Biochemistry on a leash: the roles of tether length and geometry in signal integration proteins.
  Biophys J, 96, 1275-1292.  
19056335 D.W.Pettigrew (2009).
Amino acid substitutions in the sugar kinase/hsp70/actin superfamily conserved ATPase core of E. coli glycerol kinase modulate allosteric ligand affinity but do not alter allosteric coupling.
  Arch Biochem Biophys, 481, 151-156.  
19260013 P.Tompa, M.Fuxreiter, C.J.Oldfield, I.Simon, A.K.Dunker, and V.N.Uversky (2009).
Close encounters of the third kind: disordered domains and the interactions of proteins.
  Bioessays, 31, 328-335.  
18612640 R.B.Dickinson (2009).
Models for actin polymerization motors.
  J Math Biol, 58, 81.  
19874150 R.Dominguez (2009).
Actin filament nucleation and elongation factors--structure-function relationships.
  Crit Rev Biochem Mol Biol, 44, 351-366.  
19846667 Y.Liang, H.Niederstrasser, M.Edwards, C.E.Jackson, and J.A.Cooper (2009).
Distinct roles for CARMIL isoforms in cell migration.
  Mol Biol Cell, 20, 5290-5305.  
18640983 B.J.Nolen, and T.D.Pollard (2008).
Structure and biochemical properties of fission yeast Arp2/3 complex lacking the Arp2 subunit.
  J Biol Chem, 283, 26490-26498.
PDB code: 3dwl
18952167 B.Sjöblom, J.Ylänne, and K.Djinović-Carugo (2008).
Novel structural insights into F-actin-binding and novel functions of calponin homology domains.
  Curr Opin Struct Biol, 18, 702-708.  
18669664 G.Rebowski, M.Boczkowska, D.B.Hayes, L.Guo, T.C.Irving, and R.Dominguez (2008).
X-ray scattering study of actin polymerization nuclei assembled by tandem W domains.
  Proc Natl Acad Sci U S A, 105, 10785-10790.  
18327913 J.K.Au, A.O.Olivares, A.Henn, W.Cao, D.Safer, and E.M.De La Cruz (2008).
Widely distributed residues in thymosin beta4 are critical for actin binding.
  Biochemistry, 47, 4181-4188.  
18689676 K.Baek, X.Liu, F.Ferron, S.Shu, E.D.Korn, and R.Dominguez (2008).
Modulation of actin structure and function by phosphorylation of Tyr-53 and profilin binding.
  Proc Natl Acad Sci U S A, 105, 11748-11753.
PDB codes: 3chw 3ci5 3cip
18462674 M.Boczkowska, G.Rebowski, M.V.Petoukhov, D.B.Hayes, D.I.Svergun, and R.Dominguez (2008).
X-ray scattering study of activated Arp2/3 complex with bound actin-WCA.
  Structure, 16, 695-704.  
18172428 M.E.Quinlan, and E.Kerkhoff (2008).
Actin nucleation: bacteria get in-Spired.
  Nat Cell Biol, 10, 13-15.  
19008859 S.Mouilleron, S.Guettler, C.A.Langer, R.Treisman, and N.Q.McDonald (2008).
Molecular basis for G-actin binding to RPEL motifs from the serum response factor coactivator MAL.
  EMBO J, 27, 3198-3208.
PDB codes: 2v51 2v52
18938176 U.B.Nair, P.B.Joel, Q.Wan, S.Lowey, M.A.Rould, and K.M.Trybus (2008).
Crystal structures of monomeric actin bound to cytochalasin D.
  J Mol Biol, 384, 848-864.
PDB codes: 3eks 3eku 3el2
18692583 U.Manor, and B.Kachar (2008).
Dynamic length regulation of sensory stereocilia.
  Semin Cell Dev Biol, 19, 502-510.  
18326652 V.Delatour, E.Helfer, D.Didry, K.H.Lê, J.F.Gaucher, M.F.Carlier, and G.Romet-Lemonne (2008).
Arp2/3 controls the motile behavior of N-WASP-functionalized GUVs and modulates N-WASP surface distribution by mediating transient links with actin filaments.
  Biophys J, 94, 4890-4905.  
18625842 V.O.Paavilainen, E.Oksanen, A.Goldman, and P.Lappalainen (2008).
Structure of the actin-depolymerizing factor homology domain in complex with actin.
  J Cell Biol, 182, 51-59.
PDB code: 3daw
17942696 A.D.Liverman, H.C.Cheng, J.E.Trosky, D.W.Leung, M.L.Yarbrough, D.L.Burdette, M.K.Rosen, and K.Orth (2007).
Arp2/3-independent assembly of actin by Vibrio type III effector VopL.
  Proc Natl Acad Sci U S A, 104, 17117-17122.  
17350575 C.Co, D.T.Wong, S.Gierke, V.Chang, and J.Taunton (2007).
Mechanism of actin network attachment to moving membranes: barbed end capture by N-WASP WH2 domains.
  Cell, 128, 901-913.  
17914456 F.Ferron, G.Rebowski, S.H.Lee, and R.Dominguez (2007).
Structural basis for the recruitment of profilin-actin complexes during filament elongation by Ena/VASP.
  EMBO J, 26, 4597-4606.
PDB codes: 2pav 2pbd
17434124 J.F.Swain, G.Dinler, R.Sivendran, D.L.Montgomery, M.Stotz, and L.M.Gierasch (2007).
Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker.
  Mol Cell, 26, 27-39.  
17468230 J.K.Au, E.M.De La Cruz, and D.Safer (2007).
Contributions from all over: widely distributed residues in thymosin beta-4 affect the kinetics and stability of actin binding.
  Ann N Y Acad Sci, 1112, 38-44.  
17497115 L.M.Machesky, and S.A.Johnston (2007).
MIM: a multifunctional scaffold protein.
  J Mol Med, 85, 569-576.  
18042452 M.Bosch, K.H.Le, B.Bugyi, J.J.Correia, L.Renault, and M.F.Carlier (2007).
Analysis of the function of Spire in actin assembly and its synergy with formin and profilin.
  Mol Cell, 28, 555-568.  
17947587 M.F.Carlier, M.Hertzog, D.Didry, L.Renault, F.X.Cantrelle, C.van Heijenoort, M.Knossow, and E.Guittet (2007).
Structure, function, and evolution of the beta-thymosin/WH2 (WASP-Homology2) actin-binding module.
  Ann N Y Acad Sci, 1112, 67-75.  
17956734 R.Ahuja, R.Pinyol, N.Reichenbach, L.Custer, J.Klingensmith, M.M.Kessels, and B.Qualmann (2007).
Cordon-bleu is an actin nucleation factor and controls neuronal morphology.
  Cell, 131, 337-350.  
17468236 R.Dominguez (2007).
The beta-thymosin/WH2 fold: multifunctionality and structure.
  Ann N Y Acad Sci, 1112, 86-94.  
17911258 S.H.Lee, D.B.Hayes, G.Rebowski, I.Tardieux, and R.Dominguez (2007).
Toxofilin from Toxoplasma gondii forms a ternary complex with an antiparallel actin dimer.
  Proc Natl Acad Sci U S A, 104, 16122-16127.
PDB code: 2q97
17292833 S.H.Lee, F.Kerff, D.Chereau, F.Ferron, A.Klug, and R.Dominguez (2007).
Structural basis for the actin-binding function of missing-in-metastasis.
  Structure, 15, 145-155.
PDB codes: 2d1k 2d1l
17477841 T.D.Pollard (2007).
Regulation of actin filament assembly by Arp2/3 complex and formins.
  Annu Rev Biophys Biomol Struct, 36, 451-477.  
17526584 X.Zheng, K.Diraviyam, and D.Sept (2007).
Nucleotide effects on the structure and dynamics of actin.
  Biophys J, 93, 1277-1283.  
16403731 A.E.Kelly, H.Kranitz, V.Dötsch, and R.D.Mullins (2006).
Actin binding to the central domain of WASP/Scar proteins plays a critical role in the activation of the Arp2/3 complex.
  J Biol Chem, 281, 10589-10597.  
16531231 A.H.Aguda, B.Xue, E.Irobi, T.Préat, and R.C.Robinson (2006).
The structural basis of actin interaction with multiple WH2/beta-thymosin motif-containing proteins.
  Structure, 14, 469-476.
PDB codes: 2ff3 2ff6
16990851 E.D.Goley, and M.D.Welch (2006).
The ARP2/3 complex: an actin nucleator comes of age.
  Nat Rev Mol Cell Biol, 7, 713-726.  
  16896366 F.S.Willard (2006).
Does WAVE1 contain a GoLoco/GPR motif?
  Int J Biol Sci, 2, 194-196.  
16731556 R.B.Dickinson, and D.L.Purich (2006).
Diffusion rate limitations in actin-based propulsion of hard and deformable particles.
  Biophys J, 91, 1548-1563.  
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.