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J. Biol. Chem., Vol. 277, Issue 45, 43089-43095, November 8, 2002
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From the Programs in Twinfilin is an evolutionarily conserved actin
monomer-binding protein that regulates cytoskeletal dynamics in
organisms from yeast to mammals. It is composed of two
actin-depolymerization factor homology (ADF-H) domains that show
~20% sequence identity to ADF/cofilin proteins. In contrast to
ADF/cofilins, which bind both G-actin and F-actin and promote filament
depolymerization, twinfilin interacts only with G-actin. To elucidate
the molecular mechanisms of twinfilin-actin monomer interaction, we
determined the crystal structure of the N-terminal ADF-H domain
of twinfilin and mapped its actin-binding site by site-directed
mutagenesis. This domain has similar overall structure to ADF/cofilins,
and the regions important for actin monomer binding in ADF/cofilins are
especially well conserved in twinfilin. Mutagenesis studies show that
the N-terminal ADF-H domain of twinfilin and ADF/cofilins also interact
with actin monomers through similar interfaces, although the binding
surface is slightly extended in twinfilin. In contrast, the regions
important for actin-filament interactions in ADF/cofilins are
structurally different in twinfilin. This explains the differences in
actin-interactions (monomer versus filament binding)
between twinfilin and ADF/cofilins. Taken together, our data show that
the ADF-H domain is a structurally conserved actin-binding motif and
that relatively small structural differences at the actin interfaces of
this domain are responsible for the functional variation between the
different classes of ADF-H domain proteins.
The atomic coordinates and the structure factors (code 1M4J) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
Structural Conservation between the Actin Monomer-binding
Sites of Twinfilin and Actin-depolymerizing Factor (ADF)/Cofilin*
§,,,
,, and**
Cellular Biotechnology, and
¶ Structural Biology and Biophysics, Institute of
Biotechnology, P.O. Box 56, University of Helsinki, 00014 Helsinki,
Finland and the European Molecular Biology Laboratory
(EMBL)-Hamburg Outstation, Notkestr. 85, 22603 Hamburg, Germany
*
This work was supported by grants from the Academy of
Finland, Biocentrum Helsinki, and the European Molecular Biology (EMBO) Young Investigator Program (to P. L.). Access to the beam lines at
European Molecular Biology Laboratory (EMBL)/Deutsches Elektronen Synchrotron (DESY), Hamburg, was supported by the contract
HPRI-1999-00017 by the European Commission.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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