The human formin FHOD1 contains a bipartite structure of FH3 and GTPase-binding domains required for activation

Structure. 2008 Sep 10;16(9):1313-23. doi: 10.1016/j.str.2008.06.008.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Armadillo Domain Proteins / chemistry
  • Armadillo Domain Proteins / genetics
  • Armadillo Domain Proteins / metabolism
  • Conserved Sequence / genetics
  • Enzyme Activation
  • Fetal Proteins / chemistry*
  • Fetal Proteins / genetics
  • Fetal Proteins / metabolism*
  • Formins
  • GTP Phosphohydrolases / metabolism*
  • Humans
  • Mice
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense / physiology
  • NIH 3T3 Cells
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding / physiology
  • Protein Structure, Tertiary / genetics
  • Sequence Homology, Amino Acid
  • Transfection

Substances

  • Armadillo Domain Proteins
  • FHOD1 protein, human
  • Fetal Proteins
  • Formins
  • Nuclear Proteins
  • GTP Phosphohydrolases