User:Cellular Biochemistry II/formin

Formins are cytoskeleton-organizing proteins. They are a actin filament nucleators/cappers and also have an impact on microtubules. They are present in fungi, plants and initiate the formation of actin filaments by facilitating the formation of an actin dimer/trimer which can be extended to a longer filament. As effectors of Rho-type GTPases they play a role in regulating cytokinesis, polarized growth, intracellular membrane traffic, migration, cell-cell adhesion and filopodia and stress fiber formation. ^[1] In contrast to ARP2 and ARP3, which are actin-related proteins within the the Arp2/3 complex, formins do not contain actin-like domains, they do not remain bound to the pointed end of the filament but instead remain associated with the growing barbed end. Two FH2 domains act together for nucleating actin filaments; the FH1 domain is responsible for recruiting the heterodimeric actin-profilin complex. Many formins are regulated by autoinhibition and are activated through Rho-GTPases. ^[2]

Function

Formins are important in the following processes:

Actin Filament Nucleation

Spontaneous actin filament formation is inhibited by actin-monomer-binding proteins, which prevent the formation of small oligomers as well as the instability of these oligomers. ^[3] Therefore the first step of forming a dimer or trimer is the rate-limiting step of actin filament formation. ^[4] Formins were shown to stimulate the assembly of unbranched filaments in vitro and of actin cables in vivo, ^[1] probably by stabilizing the dimer or trimer. ^[2] The ability of FH2 dimers to form a stable complex with two actins and the finding of this association in crystal structure support this mechanism. ^[5]

Actin Filament Elongation/Capping

Formins remain associated with the barbed end of the actin filament, a process called progressive capping, since it is this end, where new monomers are added to the filament. In this way the formin always caps the newly elongated barbed end. The current model for this process is the stair-stepping model: ^[2] The formin dimer lies as a donut shaped ring around the end of the filament. The two FH2 domains are each associated with two actin subunits, one of which is the same for both. The flexibility of the dimer allows the protein to move along with the growing end. The very flexible FH1 domains recruit profilin bound actin and thereby enhance the rate of subunit addition. Formins are believed to exist in an open or closed state. In the open state they allow for subunit addition, whereby the rate depends on the respective formin. In the closed state formins do not elongate actin but and act as capping proteins. ^[6]

Other

Formins have been shown to be implicated in microtubule-mediated processes in mouse cells as well as budding and fission yeast. In dividing mouse cells FMN2 is needed for proper spindle alignment, in non-dividing mouse cells they are involved in the regulation of microtubule stability and cell migration. ^[2]
Formins attached to the barbed end that are in a closed state prevent subunit addition as well as severing of the filament and thereby protect it and allow for quick return to growth once reactivated. ^[6]
Formins also seem to have a role in filament bundling, severing and depolymerization. ^[2]

Structure and Classification

Formins are large multidomain proteins ^[4] that have three regions that are highly homologous across distant species, the formin homology domains FH1, FH2 and FH3. ^[2]
Next to FH2, the other homologous regions are important in the regulation of actin assembly and interact with other proteins. The mammalian formin genes were grouped by phylogenetic analysis of the FH2 domain, which is about 400 amino acids long and responsible for nucleation of actin polymerization. ^[3] The groups are: ^[2]
1. Diaphanous formins (Dia)
2. Formin-related proteins identified in leucocytes (FRL = FMNL, formin-like)
3. Dishevelled-associated activators of morphogenesis (DAAM)
4. Delphilin
5. “inverted” formins (INF)
6. Formin homology containing proteins (FHOD)
7. Original formins (FMN)

Diaphanous-related formins (DRFs)

These formins include group 1-3 of the mammalian formins as well as the yeast formins Bni1, Bnr1 and SepA.
The C-terminal half of these proteins is responsible for actin assembly, including the profilin-binding FH1, the actin binding FH2 as well as the diaphanous autoregulatory domain (DAD). The FH1 domain usually lies right N-terminal to the FH2 domain and contains polyproline motifs, that bind to profilin, which is present bound to the pool of ATP-bound actin monomers. The N-terminal half is a the regulatory region and consists of the GTPase binding domain (GBD), the diaphanous inhibitory domain (DID), the dimerization domain (DD) and a coiled-coil region (CC). ^[2]

Regulation

mDia

mDia is a mammalian homologue of Drosophila diaphanous. mDia1 and mDia2 are required for cytokinesis, stress fiber formation, and transcriptional activation of the serum response factor. The DAD (20-30 amino acids) binds to DID (about 250 amino acids) with a very high affinity. This interaction leads to an autoinibition so that the FH2 is inactiv. Upon binding of Rho-GTP to a region including the GBD as well as a portion of the DID, ^[6]
the interaction of DAD and DID is inhibited and thus the autoinhibition removed. ^[2]. Other DRFs probably have similar mechanisms, formins not containing the DID and DAD sequence, must be regulated differently. ^[6]

References

^ ^a ^b D. Pruyne, M. Evangelista, C. Yang, E. Bi, S. Zigmond, A. Bretscher, C. Boone (july 2007). "Role of Formins in Actin Assembly: Nucleation and Barbed-End Association". Science. 297: 612–615. {{cite journal}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ B. L. Goode, M. J. Eck (2007). "Mechanism and Function of Formins in the Control of Actin Assembly". Annual Review of Biochemistry. 76: 593–627. doi:10.1146/annurev.biochem.75.103004.142647.
^ ^a ^b M. E. Quinlan, E. Kerkhoff (january 2008). "Actin nucleation: bacteria get in-Spired". Nature Cell Biology. 10: 13–15. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b F. Chang, M. Peter (july 2002). "Formins Set the Record Straight". Science. 297: 531–532. {{cite journal}}: Check date values in: |date= (help)
^ T. D. Pollard (2007). "Regulation of Actin Filament Assembly by Arp2/3 Complex and Formins". Annual Review of Biochemistry. 36: 451–77. doi:10.1146/annurev.biophys.35.040405.101936.
^ ^a ^b ^c ^d D. R. Kovar (2006). "Molecular details of formin-mediated actin assembly". Current Opinion in Cell Biology. 18: 11–17. doi:0.1016/j.ceb.2005.12.011. {{cite journal}}: Check |doi= value (help)

[Pruyne-1] D. Pruyne, M. Evangelista, C. Yang, E. Bi, S. Zigmond, A. Bretscher, C. Boone (july 2007). "Role of Formins in Actin Assembly: Nucleation and Barbed-End Association". Science. 297: 612–615. {{cite journal}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link)

[Goode-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ B. L. Goode, M. J. Eck (2007). "Mechanism and Function of Formins in the Control of Actin Assembly". Annual Review of Biochemistry. 76: 593–627. doi:10.1146/annurev.biochem.75.103004.142647.

[Quinlan-3] M. E. Quinlan, E. Kerkhoff (january 2008). "Actin nucleation: bacteria get in-Spired". Nature Cell Biology. 10: 13–15. {{cite journal}}: Check date values in: |date= (help)

[Chang-4] F. Chang, M. Peter (july 2002). "Formins Set the Record Straight". Science. 297: 531–532. {{cite journal}}: Check date values in: |date= (help)

[Pollard-5] T. D. Pollard (2007). "Regulation of Actin Filament Assembly by Arp2/3 Complex and Formins". Annual Review of Biochemistry. 36: 451–77. doi:10.1146/annurev.biophys.35.040405.101936.

[Kovar-6] D. R. Kovar (2006). "Molecular details of formin-mediated actin assembly". Current Opinion in Cell Biology. 18: 11–17. doi:0.1016/j.ceb.2005.12.011. {{cite journal}}: Check |doi= value (help)

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