Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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ADF Actin depolymerisation factor/cofilin -like domains

SMART accession number:	SM00102
Description:	Severs actin filaments and binds to actin monomers.
Interpro abstract (IPR002108):	The actin-depolymerising factor homology (ADF-H) domain is an ~150-amino acid motif that is present in three phylogenetically distinct classes of eukaryotic actin-binding proteins [(PUBMED:9693358), (PUBMED:12207032), (PUBMED:9047337)]: ADF/cofilins, which include ADF, cofilin, destrin, actophorin, coactosin, depactin and glia maturation factors (GMFs) beta and gamma. ADF/cofilins are small actin-binding proteins composed of a single ADF-H domain. They bind both actin-monomers and filaments and promote rapid filament turnover in cells by depolymerising/fragmenting actin filaments. ADF/cofilins bind ADP-actin with higher affinity than ATP-actin and inhibit the spontaneous nucleotide exchange on actin monomers Twinfilins, which are actin monomer-binding proteins that are composed of two ADF-H domains Abp1/Drebrins, which are relatively large proteins composed of an N-terminal ADF-H domain followed by a variable region and a C-terminal SH3 domain. Abp1/Drebrins interact only with actin filaments and do not promote filament depolymerisation or fragmentation Although these proteins are biochemically distinct and play different roles in actin dynamics, they all appear to use the ADF-H domain for their interactions with actin. The ADF-H domain consists of a six-stranded mixed beta-sheet in which the four central strands (beta2-beta5) are anti-parallel and the two edge strands (beta1 and beta6) run parallel with the neighbouring strands. The sheet is surrounded by two alpha-helices on each side [(PUBMED:9693358), (PUBMED:12207032), (PUBMED:15522287)].
GO component:	intracellular (GO:0005622)
GO function:	actin binding (GO:0003779)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 1042 ADF domains in 887 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a ADF domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with ADF domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Cellular role (predicted cellular role)

• Binding / catalysis: actin-binding, actin-depolymerization

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Carlier MF
  • Control of actin dynamics.
  • Curr Opin Cell Biol. 1998; 10: 45-51
  • Display abstract

  • Actin-based motility processes are tightly linked to the rapid turnover of actin filaments. Factors that control the steady state of actin assembly, such as capping proteins and actin-depolymerizing factor/cofilin, directly affect motility. Actin-depolymerizing factor increases the treadmilling of actin filaments in vitro and in vivo. Cellular factors that are involved in linking initiation of barbed end assembly to cell signaling are being identified using Listeria monocytogenes and Saccharomyces cerevisiae as model systems.

  • Maciver SK
  • How ADF/cofilin depolymerizes actin filaments.
  • Curr Opin Cell Biol. 1998; 10: 140-4

  • Fedorov AA, Lappalainen P, Fedorov EV, Drubin DG, Almo SC
  • Structure determination of yeast cofilin.
  • Nat Struct Biol. 1997; 4: 366-9
  • Display abstract

  • Cofilin, a ubiquitous 15,000 M(r) protein, plays a central role in regulating cytoskeletal dynamics. Cofilin binds to actin monomers and filaments, and has a pH-dependent actin severing activity. The structure will allow for a detailed analysis of cofilin function.

  • Jiang CJ, Weeds AG, Khan S, Hussey PJ
  • F-actin and G-actin binding are uncoupled by mutation of conserved tyrosine residues in maize actin depolymerizing factor (ZmADF).
  • Proc Natl Acad Sci U S A. 1997; 94: 9973-8
  • Display abstract

  • Actin depolymerizing factors (ADF) are stimulus responsive actin cytoskeleton modulating proteins. They bind both monomeric actin (G-actin) and filamentous actin (F-actin) and, under certain conditions, F-actin binding is followed by filament severing. In this paper, using mutant maize ADF3 proteins, we demonstrate that the maize ADF3 binding of F-actin can be spatially distinguished from that of G-actin. One mutant, zmadf3-1, in which Tyr-103 and Ala-104 (equivalent to destrin Tyr-117 and Ala-118) have been replaced by phenylalanine and glycine, respectively, binds more weakly to both G-actin and F-actin compared with maize ADF3. A second mutant, zmadf3-2, in which both Tyr-67 and Tyr-70 are replaced by phenylalanine, shows an affinity for G-actin similar to maize ADF3, but F-actin binding is abolished. The two tyrosines, Tyr-67 and Tyr-70, are in the equivalent position to Tyr-82 and Tyr-85 of destrin, respectively. Using the tertiary structure of destrin, yeast cofilin, and Acanthamoeba actophorin, we discuss the implications of removing the aromatic hydroxyls of Tyr-82 and Tyr-85 (i.e., the effect of substituting phenylalanine for tyrosine) and conclude that Tyr-82 plays a critical role in stabilizing the tertiary structure that is essential for F-actin binding. We propose that this tertiary structure is maintained as a result of a hydrogen bond between the hydroxyl of Tyr-82 and the carbonyl of Tyr-117, which is located in the long alpha-helix; amino acid components of this helix (Leu-111 to Phe-128) have been implicated in G-actin and F-actin binding. The structures of human destrin and yeast cofilin indicate a hydrogen distance of 2.61 and 2.77 A, respectively, with corresponding bond angles of 99.5 degrees and 113 degrees, close to the optimum for a strong hydrogen bond.

  • Lappalainen P, Drubin DG
  • Cofilin promotes rapid actin filament turnover in vivo.
  • Nature. 1997; 388: 78-82
  • Display abstract

  • The ability of actin filaments to function in cell morphogenesis and motility is coupled to their capacity for rapid assembly and disassembly. Because disassembly in vitro is much slower than in vivo, cellular factors that stimulate disassembly have long been assumed to exist. Although numerous proteins can affect actin dynamics in vitro, demonstration of in vivo relevance of these effects has not been achieved. We have used genetics and an actin-inhibitor in yeast to demonstrate that rapid cycles of actin assembly and disassembly depend on the small actin-binding protein cofilin, and that cofilin stimulates filament disassembly. These results may explain why cofilin is ubiquitous in eukaryotes and is essential for viability in every organism in which its function has been tested genetically. Magnitudes of disassembly defects in cofilin mutants in vivo were found to be correlated closely with the magnitudes of disassembly defects observed in vitro, supporting our conclusions. Furthermore, these cofilin mutants provided an opportunity to distinguish in living cells those actin functions that depend specifically on filament turnover (endocytosis) from those that do not (cortical actin patch motility).

  • Lappalainen P, Fedorov EV, Fedorov AA, Almo SC, Drubin DG
  • Essential functions and actin-binding surfaces of yeast cofilin revealed by systematic mutagenesis.
  • EMBO J. 1997; 16: 5520-30
  • Display abstract

  • Cofilin stimulates actin filament turnover in vivo. The phenotypes of twenty yeast cofilin mutants generated by systematic mutagenesis were determined. Ten grew as well as the wild type and showed no cytoskeleton defects, seven were recessive-lethal and three were conditional-lethal and caused severe actin organization defects. Biochemical characterization of interactions between nine mutant yeast cofilins and yeast actin provided evidence that F-actin binding and depolymerization are essential cofilin functions. Locating the mutated residues on the yeast cofilin molecular structure allowed several important conclusions to be drawn. First, residues required for actin monomer binding are proximal to each other. Secondly, additional residues are required for interactions with actin filaments; these residues might bind an adjacent subunit in the actin filament. Thirdly, despite striking structural similarity, cofilin interacts with actin in a different manner from gelsolin segment-1. Fourthly, a previously unrecognized cofilin function or interaction is suggested by identification of spatially proximal residues important for cofilin function in vivo, but not for actin interactions in vitro. Finally, mutation of the cofilin N-terminus suggests that its sequence is conserved because of its critical role in actin interactions, not because it is sometimes a target for protein kinases.

  • Leonard SA, Gittis AG, Petrella EC, Pollard TD, Lattman EE
  • Crystal structure of the actin-binding protein actophorin from Acanthamoeba.
  • Nat Struct Biol. 1997; 4: 369-73
  • Display abstract

  • Actophorin is a member of the actin-depolymerizing factor/cofilin family. It severs actin filaments and sequesters actin monomers. The crystal structure of actophorin will help to elucidate actin-ADF/cofilin interactions.

  • Abe H, Endo T, Yamamoto K, Obinata T
  • Sequence of cDNAs encoding actin depolymerizing factor and cofilin of embryonic chicken skeletal muscle: two functionally distinct actin-regulatory proteins exhibit high structural homology.
  • Biochemistry. 1990; 29: 7420-5
  • Display abstract

  • Two actin-regulatory proteins of 19 and 20 kDa are involved in the regulation of actin assembly in developing chicken skeletal muscle. They are homologous with actin depolymerizing factor (ADF) and cofilin, a pH-dependent actin-modulating protein, which were originally discovered in chicken and mammalian brain, respectively. In this study, full-length cDNA clones were isolated by screening a lambda gt11 cDNA library constructed from poly(A+) RNA of embryonic chicken skeletal muscle with the antibodies specific for each protein, and their complete sequences were determined. The chicken cofilin cDNA encoded a protein of 166 amino acids, the sequence of which had over 80% identity with that of porcine brain cofilin. The amino acid sequence of the ADF was 165 amino acids and showed about 70% identity with either chicken or mammalian cofilin, in spite of the fact that ADF and cofilin are functionally distinct. Like chicken and mammalian cofilin, ADF contained a sequence similar to the nuclear transport signal sequence of SV40 large T antigen. ADF and cofilin shared a hexapeptide identical with the amino-terminal sequence of tropomyosin as well as the regions homologous to other actin-regulatory proteins, including depactin, gelsolin, and profilin. The overall nucleotide sequences and Southern blot analysis of genomic DNA, however, indicated that the two proteins were derived from different genes.

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 50.00 map04810 Regulation of actin cytoskeleton 50.00 map04360 Axon guidance This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with ADF domain which could be assigned to a KEGG orthologous group, and not all proteins containing ADF domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of ADF domains in PDB

  PDB code	Main view	Title
  1ahq		Recombinant actophorin
  1ak6		Destrin, nmr, minimized average structure
  1ak7		Destrin, nmr, 20 structures
  1cfy		Yeast cofilin, monoclinic crystal form
  1cnu		Phosphorylated actophorin from acantamoeba polyphaga
  1cof		Yeast cofilin, orthorhombic crystal form
  1f7s		Crystal structure of adf1 from arabidopsis thaliana
  1hqz		Cofilin homology domain of a yeast actin-binding protein abp1p
  1m4j		Crystal structure of the n-terminal adf-h domain of mouse twinfilin isoform-1
  1q8g		Nmr structure of human cofilin
  1q8x		Nmr structure of human cofilin
  1qpv		Yeast cofilin
  1t2l		Three crystal structures of human coactosin-like protein
  1t3x		Three crystal structures of human coactosin-like protein
  1t3y		Three crystal structures of human coactosin-like protein
  1tmw		Solution structure of human coactosin like protein d123n
  1tvj		Solution structure of chick cofilin
  1udm		Solution structure of coactosin-like protein (cofilin family) from mus musculus
  1v6f		Solution structure of glia maturation factor-beta from mus musculus
  1vfq		The crystal structure of human coactosin-like protein at 1.9 a resolution
  1vkk		Crystal structure of glia maturation factor-gamma (gmfg) from mus musculus at 1.50 a resolution
  1wfs		Solution structure of glia maturation factor-gamma from mus musculus
  1wm4		Solution structure of mouse coactosin, an actin filament binding protein
  1wnj		Nmr structure of human coactosin-like protein
  1x67		Solution structure of the cofilin homology domain of hip-55 (drebrin-like protein)
  2d8b		Solution structure of the second tandem cofilin-domain of mouse twinfilin
  2hd7		Solution structure of c-teminal domain of twinfilin-1.
  2i2q		Fission yeast cofilin
  2vac		Structure of n-terminal actin depolymerizing factor homology (adf-h) domain of human twinfilin-2
  2w0i		Structure of c-terminal actin depolymerizing factor homology (adf-h) domain of human twinfilin-2
  3daw		Structure of the actin-depolymerizing factor homology domain in complex with actin

• Links (links to other resources describing this domain)

• BLOCKS	COFILIN
  PFAM	cofilin_ADF
  INTERPRO	IPR002108

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