Formins

{{Short description|Proteins}} {{cs1 config|name-list-style=vanc}} {{infobox protein |Name=formin 1 |caption= |image= |width= |HGNCid=3768 |Symbol=FMN1 |AltSymbols=LD, FMN |EntrezGene=342184 |OMIM=136535 |RefSeq=NM_001103184 |UniProt= Q68DA7 |PDB= |ECnumber= |Chromosome=15 |Arm=q |Band=13 |LocusSupplementaryData=-q14 }} {{Infobox protein family | Symbol = Drf_FH1 | Name = Formin Homology Region 1 | image = | width = | caption = | Pfam = PF06346 | Pfam_clan = | InterPro = IPR009408 | SMART = | PROSITE = | MEROPS = | SCOP = | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }} thumb|left|Domain structure of formin proteins across phyla.<ref name="Chalkia">{{cite journal | vauthors = Chalkia D, Nikolaidis N, Makalowski W, Klein J, Nei M | title = Origins and evolution of the formin multigene family that is involved in the formation of actin filaments | journal = Molecular Biology and Evolution | volume = 25 | issue = 12 | pages = 2717–33 | date = December 2008 | pmid = 18840602 | pmc = 2721555 | doi = 10.1093/molbev/msn215 }}</ref> {{Infobox protein family | Symbol = FH2 | Name = Formin Homology 2 Domain | image = PDB 1ux4 EBI.jpg | width = | caption = crystal structures of a formin homology-2 domain reveal a tethered-dimer architecture | Pfam = PF02181 | Pfam_clan = | InterPro = IPR015425 | SMART = FH2 | PROSITE = | MEROPS = | SCOP = 1ux5 | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }} {{Infobox protein family | Symbol = Drf_FH3 | Name = Diaphanous FH3 Domain | image = PDB 1z2c EBI.jpg | width = | caption = crystal structure of mdia1 gbd-fh3 in complex with rhoc-gmppnp | Pfam = PF06367 | Pfam_clan = CL0020 | InterPro = IPR010472 | SMART = | PROSITE = | MEROPS = | SCOP = | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }} {{Infobox protein family | Symbol = Drf_DAD | Name = DRF Autoregulatory Domain | image = PDB 2bap EBI.jpg | width = | caption = crystal structure of the n-terminal mdia1 armadillo repeat region and dimerisation domain in complex with the mdia1 autoregulatory domain (dad) | Pfam = PF06345 | Pfam_clan = | InterPro = IPR010465 | SMART = | PROSITE = | MEROPS = | SCOP = | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }} {{Infobox protein family | Symbol = Drf_GBD | Name = Diaphanous GTPase-binding Domain | image = PDB 1z2c EBI.jpg | width = | caption = crystal structure of mdia1 gbd-fh3 in complex with rhoc-gmppnp | Pfam = PF06371 | Pfam_clan = CL0020 | InterPro = IPR010473 | SMART = | PROSITE = | MEROPS = | SCOP = | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }} '''Formins (formin homology proteins)''' are a group of proteins that are involved in the polymerization of actin and associate with the fast-growing end (barbed end) of actin filaments.<ref>{{cite journal | vauthors = Evangelista M, Zigmond S, Boone C | title = Formins: signaling effectors for assembly and polarization of actin filaments | journal = Journal of Cell Science | volume = 116 | issue = Pt 13 | pages = 2603–11 | date = July 2003 | pmid = 12775772 | doi = 10.1242/jcs.00611 | doi-access = free }}</ref> Most formins are Rho-GTPase effector proteins. Formins regulate the actin and microtubule cytoskeleton <ref name="pmid25788699">{{cite journal | vauthors = Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC | title = The evolution of compositionally and functionally distinct actin filaments | journal = Journal of Cell Science | volume = 128 | issue = 11 | pages = 2009–19 | date = June 2015 | pmid = 25788699 | doi = 10.1242/jcs.165563 | doi-access = free }}</ref><ref name="pmid17373907">{{cite journal | vauthors = Goode BL, Eck MJ | title = Mechanism and function of formins in the control of actin assembly | journal = Annual Review of Biochemistry | volume = 76 | pages = 593–627 | year = 2007 | pmid = 17373907 | doi = 10.1146/annurev.biochem.75.103004.142647 }}</ref> and are involved in various cellular functions such as cell polarity, cytokinesis, cell migration and SRF transcriptional activity.<ref name="pmid16740473">{{cite journal | vauthors = Faix J, Grosse R | title = Staying in shape with formins | journal = Developmental Cell | volume = 10 | issue = 6 | pages = 693–706 | date = June 2006 | pmid = 16740473 | doi = 10.1016/j.devcel.2006.05.001 | doi-access = free }}</ref> Formins are multidomain proteins that interact with diverse signalling molecules and cytoskeletal proteins, although some formins have been assigned functions within the nucleus.

== Diversity ==

Formins have been found in all eukaryotes studied.<ref name="Chalkia"/> In humans, 15 different formin proteins are present that have been classified in 7 subgroups.<ref>{{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 }}</ref> By contrast, yeasts contain only 2-3 formins.<ref name="Baarlink">{{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 }}</ref>

== Structure and interactions == 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.<ref name="pmid12538772">{{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 }}</ref><ref>{{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 }}</ref> 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,<ref>{{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}}</ref> SH3 (Src homology 3) domain proteins,<ref name="Uetz">{{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 }}</ref> and WW domain proteins. The actin nucleation-promoting activity of ''S. cerevisiae'' formins has been localized to the FH2 domain.<ref name="pmid17373907" /> 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.<ref name="pmid14576350">{{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 }}</ref><ref name="pmid14992721">{{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 }}</ref> 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 cellular conjugation.<ref name="pmid11171383">{{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 }}</ref><ref name="pmid9606213">{{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 }}</ref> 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.<ref name="pmid12676083">{{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 }}</ref> 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.<ref name="pmid12676083" /> 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.<ref name="pmid15006353">{{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 }}</ref><ref>{{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 }}</ref>

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.<ref name="PMID11483957">{{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 }}</ref><ref name="PMID19631698">{{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 }}</ref>

== See also == *Formin-2

== References == {{reflist}}

== External links == * {{usurped|1=[https://web.archive.org/web/20140227184833/http://www.mechanobio.info/modules/go-0070649 MBInfo - Formin mediated actin nucleation]}}

Category:Protein domains Category:Cell biology Category:Proteins Category:Cellular processes