The human formin FHOD1 contains a bipartite structure of FH3 and GTPase-binding domains required for activation.
Formins induce the nucleation and polymerization of unbranched actin filaments. They share three homology domains required for profilin binding, actin polymerization, and regulation. Diaphanous-related formins (DRFs) are activated by GTPases of the Rho/Rac family, whose interaction with the N-terminal formin domain is thought to displace a C-terminal Diaphanous-autoregulatory domain (DAD). We have determined the structure of the N-terminal domains of FHOD1 consisting of a GTPase-binding domain (GBD) and the DAD-recognition domain FH3. In contrast to the formin mDia1, the FHOD1-GBD reveals a ubiquitin superfold as found similarly in c-Raf1 or PI3 kinase. This GBD is recruited by Rac and Ras GTPases in cells and plays an essential role for FHOD1-mediated actin remodeling. The FHOD1-FH3 domain is composed of five armadillo repeats, similarly to other formins. Mutation of one residue in the predicted DAD-interaction surface efficiently activates FHOD1 in cells. These results demonstrate that DRFs have evolved different molecular solutions to govern their autoregulation and GTPase specificity.
Schulte
Antje
A
Abteilung Physikalische Biochemie, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Stolp
Bettina
B
Schönichen
André
A
Pylypenko
Olena
O
Rak
Alexey
A
Fackler
Oliver T
OT
Geyer
Matthias
M
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D051186:Armadillo Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D004789:Enzyme Activation; D005326:Fetal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000080865:Formins; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000502:physiology; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D051186:Armadillo Domain Proteins; C120021:FHOD1 protein, human; D005326:Fetal Proteins; D000080865:Formins; D009687:Nuclear Proteins; D020558:GTP Phosphohydrolases