Formins

Formins have been found in all eukaryotes studied. In humans, 15 different formin proteins are present that have been classified in 7 subgroups.{{cite journal | vauthors = Higgs HN, Peterson KJ | title = Phylogenetic analysis of the formin homology 2 domain | journal = Molecular Biology of the Cell | volume = 16 | issue = 1 | pages = 1–13 | date = January 2005 | pmid = 15509653 | pmc = 539145 | doi = 10.1091/mbc.E04-07-0565 }} By contrast, yeasts contain only 2-3 formins.{{cite journal | vauthors = Baarlink C, Brandt D, Grosse R | title = SnapShot: Formins | journal = Cell | volume = 142 | issue = 1 | pages = 172–172.e1 | date = July 2010 | pmid = 20603022 | doi = 10.1016/j.cell.2010.06.030 | s2cid = 2914004 | doi-access = free }}

Formins are characterized by the presence of three formin homology (FH) domains (FH1, FH2 and FH3), although members of the formin family do not necessarily contain all three domains.{{cite journal | vauthors = Kitayama C, Uyeda TQ | title = ForC, a novel type of formin family protein lacking an FH1 domain, is involved in multicellular development in Dictyostelium discoideum | journal = Journal of Cell Science | volume = 116 | issue = Pt 4 | pages = 711–23 | date = February 2003 | pmid = 12538772 | doi = 10.1242/jcs.00265 | doi-access = free }}{{cite journal | vauthors = Wallar BJ, Alberts AS | title = The formins: active scaffolds that remodel the cytoskeleton | journal = Trends in Cell Biology | volume = 13 | issue = 8 | pages = 435–46 | date = August 2003 | pmid = 12888296 | doi = 10.1016/S0962-8924(03)00153-3 }} In addition, other domains are usually present, such as PDZ, DAD, WH2, or FHA domains.

The proline-rich FH1 domain mediates interactions with a variety of proteins, including the actin-binding protein profilin,{{Cite book |last=Uetz |first=Peter |url=https://libcatalog.embl.de/cgi-bin/koha/opac-detail.pl?biblionumber=8953 |title=Biochemische Studien am limb deformity-Protein der Vertebraten: Inaugural-Dissertation zur Erlangung der Doktorwürde der Naturwissenschaftlich-Mathematischen Gesamtfakultät der Ruprecht-Karls-Universität Heidelberg |date=1997 |publisher=European Molecular Biology Laboratory |others=Developmental Biology, European Molecular Biology Laboratory |location=Heidelberg}} SH3 (Src homology 3) domain proteins,{{cite journal | vauthors = Uetz P, Fumagalli S, James D, Zeller R | title = Molecular interaction between limb deformity proteins (formins) and Src family kinases | journal = The Journal of Biological Chemistry | volume = 271 | issue = 52 | pages = 33525–30 | date = December 1996 | pmid = 8969217 | doi = 10.1074/jbc.271.52.33525 | doi-access = free }} and WW domain proteins. The actin nucleation-promoting activity of S. cerevisiae formins has been localized to the FH2 domain. The FH2 domain is required for the self-association of formin proteins through the ability of FH2 domains to directly bind each other, and may also act to inhibit actin polymerization.{{cite journal | vauthors = Takeya R, Sumimoto H | title = 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 | journal = Journal of Cell Science | volume = 116 | issue = Pt 22 | pages = 4567–75 | date = November 2003 | pmid = 14576350 | doi = 10.1242/jcs.00769 | doi-access = free }}{{cite journal | vauthors = Shimada A, Nyitrai M, Vetter IR, Kühlmann D, Bugyi B, Narumiya S, Geeves MA, Wittinghofer A | title = The core FH2 domain of diaphanous-related formins is an elongated actin binding protein that inhibits polymerization | journal = Molecular Cell | volume = 13 | issue = 4 | pages = 511–22 | date = February 2004 | pmid = 14992721 | doi = 10.1016/S1097-2765(04)00059-0 | doi-access = free }} The FH3 domain is less well conserved and is required for directing formins to the correct intracellular location, such as the mitotic spindle, or the projection tip during conjugation.{{cite journal | vauthors = Kato T, Watanabe N, Morishima Y, Fujita A, Ishizaki T, Narumiya S | title = Localization of a mammalian homolog of diaphanous, mDia1, to the mitotic spindle in HeLa cells | journal = Journal of Cell Science | volume = 114 | issue = Pt 4 | pages = 775–84 | date = February 2001 | doi = 10.1242/jcs.114.4.775 | pmid = 11171383 | hdl = 2433/150544 | hdl-access = free }}{{cite journal | vauthors = Petersen J, Nielsen O, Egel R, Hagan IM | title = FH3, a domain found in formins, targets the fission yeast formin Fus1 to the projection tip during conjugation | journal = The Journal of Cell Biology | volume = 141 | issue = 5 | pages = 1217–28 | date = June 1998 | pmid = 9606213 | pmc = 2137179 | doi = 10.1083/jcb.141.5.1217 }} In addition, some formins can contain a GTPase-binding domain (GBD) required for binding to Rho small GTPases, and a C-terminal conserved Dia-autoregulatory domain (DAD). The GBD is a bifunctional autoinhibitory domain that interacts with and is regulated by activated Rho family members. Mammalian Drf3 contains a CRIB-like motif within its GBD for binding to Cdc42, which is required for Cdc42 to activate and guide Drf3 towards the cell cortex where it remodels the actin skeleton.{{cite journal | vauthors = Peng J, Wallar BJ, Flanders A, Swiatek PJ, Alberts AS | title = Disruption of the Diaphanous-related formin Drf1 gene encoding mDia1 reveals a role for Drf3 as an effector for Cdc42 | journal = Current Biology | volume = 13 | issue = 7 | pages = 534–45 | date = April 2003 | pmid = 12676083 | doi = 10.1016/S0960-9822(03)00170-2 | s2cid = 13902104 | doi-access = free | bibcode = 2003CBio...13..534P }} The DAD binds the N-terminal GBD; this link is broken when GTP-bound Rho binds to the GBD and activates the protein. The addition of the DAD to mammalian cells induces actin filament formation, stabilizes microtubules, and activates SRF mediated transcription. Another commonly found domain is an armadillo repeat region (ARR) located in the FH3 domain.

The FH2 domain, has been shown by X-ray crystallography to have an elongated, crescent shape containing three helical subdomains.{{cite journal | vauthors = Xu Y, Moseley JB, Sagot I, Poy F, Pellman D, Goode BL, Eck MJ | title = Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture | journal = Cell | volume = 116 | issue = 5 | pages = 711–23 | date = March 2004 | pmid = 15006353 | doi = 10.1016/S0092-8674(04)00210-7 | s2cid = 15855545 | doi-access = free }}{{cite journal | vauthors = Thompson ME, Heimsath EG, Gauvin TJ, Higgs HN, Kull FJ | title = FMNL3 FH2-actin structure gives insight into formin-mediated actin nucleation and elongation | journal = Nature Structural & Molecular Biology | volume = 20 | issue = 1 | pages = 111–8 | date = January 2013 | pmid = 23222643 | pmc = 3876896 | doi = 10.1038/nsmb.2462 }}

Formins also directly bind to microtubules via their FH2 domain. This interaction is important in promoting the capture and stabilization of a subset of microtubules oriented towards the leading edge of migrating cells. Formins also promote the capture of microtubules by the kinetochore during mitosis and for aligning microtubules along actin filaments.{{cite journal | vauthors = Palazzo AF, Cook TA, Alberts AS, Gundersen GG | title = mDia mediates Rho-regulated formation and orientation of stable microtubules | journal = Nature Cell Biology | volume = 3 | issue = 8 | pages = 723–9 | date = August 2001 | pmid = 11483957 | doi = 10.1038/35087035 | s2cid = 7374170 }}{{cite journal | vauthors = Bartolini F, Gundersen GG | title = Formins and microtubules | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1803 | issue = 2 | pages = 164–73 | date = February 2010 | pmid = 19631698 | pmc = 2856479 | doi = 10.1016/j.bbamcr.2009.07.006 }}

• Formin-2

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• [http://www.mechanobio.info/modules/go-0070649 MBInfo - Formin mediated actin nucleation]

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Category:Protein domains

Category:Cell biology

Category:Proteins

Category:Cellular processes