Formine

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Formin 1
other names

FMN 1

Identifier
External IDs

Formin 2
other names

FMN 2

Identifier
External IDs

Formine is a group of proteins that mainly due to the actin nucleation are involved, the actin and microtubule - cytoskeleton regulate and beyond to several different cellular functions such as cell migration or cytokinesis are involved.

Shapes and structure

The different domains of formins in different strains .
The formin FH2 domain

In general, formins are multi- domain proteins up to 2000 amino acids long , which are characterized by the presence of the three domains FH1 (“formin homology domain 1”), FH2 and FH3 . However, not all three domains have to be present for a protein to be a formin. For example, the Formin ForC found in Dictyostelium discoideum does not contain an FH1 domain. This FH1 domain is rich in proline and can therefore interact with profilin and SH3 domains or WW motifs of other proteins. The crescent-shaped FH2 domain allows the formins to bind to themselves as FH2 domains can bind to one another and consists of three helical subdomains. The FH3 domain is less well conserved and appears to be important for the localization of the formins in the cell. In addition, formins can have a GBD (“GTPase binding domain”) and a C -terminal DAD (“diaphanous autoregulatory domain”), which play a role in the regulation of formin.

Formin is found in all eukaryotes . In evolutionary terms, the FH2 domain also goes back to this.

Formin was found in 1990 in studies on mice that suffered from deformations of their limbs ("limb deformaty (LD)"), general tissue damage and variable aplasia . Richard P. Woychik and others could blame the mutations in a complex gene that they called "formin" because of its great importance for the shape of the limbs.

function

Regulation of the actin cytoskeleton

Formins are involved in the formation and regulation of the actin cytoskeleton in a variety of ways. The highly conserved FH2 domain of formin and the associated linker to the FH1 domain are necessary to stabilize the dimerization of G-actin and its nucleation to F-actin in vitro . One possible reason for this stabilization is the fact that the FH2 domain binds two actin molecules similar to the binding in F-actin. In contrast, the FH1 domain interacts with profilin and can therefore recruit ATP-actin from the profilin-G-actin complex and thus also promote nucleation. In addition, the FH2 domain of formin is also an effective counterpart to so-called "capping" proteins; these are proteins that, by attaching to the plus ends of actin, inhibit nucleation and, in contrast to formin, increase the critical actin concentration.

For a more precise process, the “leaky” / “processive cappers” model, supported by various observations, was developed, which postulates that formins are continuously associated and connected with the plus end of the actin filament. New G-actin elements are incorporated between the FH2 domain of the formin and the filament; the formins exert a force of one pico newton per actin filament.

Participation in the formation of filopodia

To explain the participation of the formins in the formation of filopodia, there is the “convergent elongation model of filopdia formation”. It states that F-actin, which has been nucleated and capped by the Arp 2/3 complex , is selectively elongated again and clusters together in bundles. These bundles eventually press against the cell's plasma membrane and lead to the formation of the filopodia. The removal of the capping on the F-actin is brought about by proteins of the Ena / VASP family, both of which are required for a functioning filopdial formation. Research suggests that formins are probably responsible for the selective elongation of F-actin.

Regulation of formins

Rho-GTPases - molecular switches of various signal transduction processes - are probably responsible for regulating the formins . The mechanism was well understood in Drosophila : If the FH1 and FH2 domains are flanked by the GBD domain ( N -terminal GTPase binding domain) and the DAD (diaphanous autoregulatory domain), then formin is inhibited. This inhibition is lifted when the GTPase binds GTP and is thus activated. In this activated state, the GTPase can bind to the GBD domain and thus dissolve the inhibitory complex around formin.

Individual evidence

  1. ^ BL Goode and MJ Eck: Mechanism and function of formins in the control of actin assembly . In: Annual Review of Biochemistry . 76, 2007, pp. 593-627. doi : 10.1146 / annurev.biochem.75.103004.142647 . PMID 17373907 .
  2. ^ Jan Faix and R. Grosse: Staying in shape with formins . In: Developmental cell . 10, No. 6, June 2006, pp. 693-706. PMID 16740473 .
  3. ↑ Chikako Kitayama and Taro QP Uyeda: ForC, a novel type of formin family protein lacking an FH1 domain, is involved in multicellular development in Dictyostelium discoideum . In: Journal of Cell Science . 116 (Pt. 4), February 2003, pp. 711-723. PMID 12538772 .
  4. ^ R. Takeya and H. Sumimoto: Fhos, a mammalian formin, directly binds to F-actin via a region N-terminal to the FH1 domain and forms a homotypic complex via the FH2 domain to promote actin fiber formation . In: Journal of Cell Science . 166 (Pt. 22), November 2003, pp. 4567-4575. doi : 10.1242 / jcs.00769 . PMID 14576350 .
  5. ^ Y. Xu, JB Moseley, I. Sagot, F. Poy, D. Pellman, BL Goode and MJ Eck: Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture . In: Cell . 116, No. 5, March 2004, pp. 711-723. doi : 10.1016 / S0092-8674 (04) 00210-7 . PMID 15006353 .
  6. ↑ InterPro : IPR015425 (English)
  7. ↑ Dimitra Chalkia, Nikolas Nikolaidis, Wojciech Makalowski, Jan Klein and Masatoshi Nei: Origins and Evolution of the Formin Multigene Family That Is Involved in the Formation of Actin Filaments . In: Molecular Biology and Evolution . 25, No. 12, December 2008, pp. 2717-2733. doi : 10.1093 / molbev / msn215 . PMC 2721555 (free full text).
  8. ↑ Richard P. Woychik, RL Maas, R. Zeller, TF Vogt and P. Leder: 'Formins': proteins deduced from the alternative transcripts of the limb deformity gene . In: Nature . 346, No. 62787, August 1990, pp. 850-853. doi : 10.1038 / 346850a0 . PMID 2392150 .
  9. ^ Formine.  In: Online Mendelian Inheritance in Man . (English)

Literature sources

  • Jan Faix: Formins and actin cytoskeleton . In: BIOspectrum . Springer, January 2006 ( biospektrum.de [PDF; accessed on August 15, 2015]).