Formins Explained

formin 1
Hgncid:3768
Symbol:FMN1
Altsymbols:LD, FMN
Entrezgene:342184
Omim:136535
Refseq:NM_001103184
Uniprot:Q68DA7
Chromosome:15
Arm:q
Band:13
Locussupplementarydata:-q14
Symbol:Drf_FH1
Formin Homology Region 1
Pfam:PF06346
Interpro:IPR009408
Symbol:FH2
Formin Homology 2 Domain
Pfam:PF02181
Interpro:IPR015425
Smart:FH2
Scop:1ux5
Symbol:Drf_FH3
Diaphanous FH3 Domain
Pfam:PF06367
Pfam Clan:CL0020
Interpro:IPR010472
Symbol:Drf_DAD
DRF Autoregulatory Domain
Pfam:PF06345
Interpro:IPR010465
Symbol:Drf_GBD
Diaphanous GTPase-binding Domain
Pfam:PF06371
Pfam Clan:CL0020
Interpro:IPR010473

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.[1] Most formins are Rho-GTPase effector proteins. Formins regulate the actin and microtubule cytoskeleton [2] [3] and are involved in various cellular functions such as cell polarity, cytokinesis, cell migration and SRF transcriptional activity.[4] 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. In humans, 15 different formin proteins are present that have been classified in 7 subgroups.[5] By contrast, yeasts contain only 2-3 formins.[6]

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.[7] [8] 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,[9] SH3 (Src homology 3) domain proteins,[10] 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.[11] [12] 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.[13] [14] 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.[15] 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.[16] [17]

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.[18] [19]

See also

External links

Notes and References

  1. Evangelista M, Zigmond S, Boone C . Formins: signaling effectors for assembly and polarization of actin filaments . Journal of Cell Science . 116 . Pt 13 . 2603–11 . July 2003 . 12775772 . 10.1242/jcs.00611 . free .
  2. Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC . The evolution of compositionally and functionally distinct actin filaments . Journal of Cell Science . 128 . 11 . 2009–19 . June 2015 . 25788699 . 10.1242/jcs.165563 . free .
  3. Goode BL, Eck MJ . Mechanism and function of formins in the control of actin assembly . Annual Review of Biochemistry . 76 . 593–627 . 2007 . 17373907 . 10.1146/annurev.biochem.75.103004.142647 .
  4. Faix J, Grosse R . Staying in shape with formins . Developmental Cell . 10 . 6 . 693–706 . June 2006 . 16740473 . 10.1016/j.devcel.2006.05.001 . free .
  5. Higgs HN, Peterson KJ . Phylogenetic analysis of the formin homology 2 domain . Molecular Biology of the Cell . 16 . 1 . 1–13 . January 2005 . 15509653 . 539145 . 10.1091/mbc.E04-07-0565 .
  6. Baarlink C, Brandt D, Grosse R . SnapShot: Formins . Cell . 142 . 1 . 172–172.e1 . July 2010 . 20603022 . 10.1016/j.cell.2010.06.030 . 2914004 . free .
  7. Kitayama C, Uyeda TQ . ForC, a novel type of formin family protein lacking an FH1 domain, is involved in multicellular development in Dictyostelium discoideum . Journal of Cell Science . 116 . Pt 4 . 711–23 . February 2003 . 12538772 . 10.1242/jcs.00265 . free .
  8. Wallar BJ, Alberts AS . The formins: active scaffolds that remodel the cytoskeleton . Trends in Cell Biology . 13 . 8 . 435–46 . August 2003 . 12888296 . 10.1016/S0962-8924(03)00153-3 .
  9. Book: Uetz, Peter . Biochemische Studien am limb deformity-Protein der Vertebraten: Inaugural-Dissertation zur Erlangung der Doktorwürde der Naturwissenschaftlich-Mathematischen Gesamtfakultät der Ruprecht-Karls-Universität Heidelberg . 1997 . European Molecular Biology Laboratory . Developmental Biology, European Molecular Biology Laboratory . Heidelberg.
  10. Uetz P, Fumagalli S, James D, Zeller R . Molecular interaction between limb deformity proteins (formins) and Src family kinases . The Journal of Biological Chemistry . 271 . 52 . 33525–30 . December 1996 . 8969217 . 10.1074/jbc.271.52.33525 . free .
  11. Takeya R, Sumimoto H . 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 of Cell Science . 116 . Pt 22 . 4567–75 . November 2003 . 14576350 . 10.1242/jcs.00769 . free .
  12. Shimada A, Nyitrai M, Vetter IR, Kühlmann D, Bugyi B, Narumiya S, Geeves MA, Wittinghofer A . The core FH2 domain of diaphanous-related formins is an elongated actin binding protein that inhibits polymerization . Molecular Cell . 13 . 4 . 511–22 . February 2004 . 14992721 . 10.1016/S1097-2765(04)00059-0 . free .
  13. Kato T, Watanabe N, Morishima Y, Fujita A, Ishizaki T, Narumiya S . Localization of a mammalian homolog of diaphanous, mDia1, to the mitotic spindle in HeLa cells . Journal of Cell Science . 114 . Pt 4 . 775–84 . February 2001 . 10.1242/jcs.114.4.775 . 11171383 . 2433/150544 . free .
  14. Petersen J, Nielsen O, Egel R, Hagan IM . FH3, a domain found in formins, targets the fission yeast formin Fus1 to the projection tip during conjugation . The Journal of Cell Biology . 141 . 5 . 1217–28 . June 1998 . 9606213 . 2137179 . 10.1083/jcb.141.5.1217 .
  15. Peng J, Wallar BJ, Flanders A, Swiatek PJ, Alberts AS . Disruption of the Diaphanous-related formin Drf1 gene encoding mDia1 reveals a role for Drf3 as an effector for Cdc42 . Current Biology . 13 . 7 . 534–45 . April 2003 . 12676083 . 10.1016/S0960-9822(03)00170-2 . 13902104 . free . 2003CBio...13..534P .
  16. Xu Y, Moseley JB, Sagot I, Poy F, Pellman D, Goode BL, Eck MJ . Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture . Cell . 116 . 5 . 711–23 . March 2004 . 15006353 . 10.1016/S0092-8674(04)00210-7 . 15855545 . free .
  17. Thompson ME, Heimsath EG, Gauvin TJ, Higgs HN, Kull FJ . FMNL3 FH2-actin structure gives insight into formin-mediated actin nucleation and elongation . Nature Structural & Molecular Biology . 20 . 1 . 111–8 . January 2013 . 23222643 . 3876896 . 10.1038/nsmb.2462 .
  18. Palazzo AF, Cook TA, Alberts AS, Gundersen GG . mDia mediates Rho-regulated formation and orientation of stable microtubules . Nature Cell Biology . 3 . 8 . 723–9 . August 2001 . 11483957 . 10.1038/35087035 . 7374170 .
  19. Bartolini F, Gundersen GG . Formins and microtubules . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1803 . 2 . 164–73 . February 2010 . 19631698 . 2856479 . 10.1016/j.bbamcr.2009.07.006 .

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