Summary: Formin Homology 2 Domain
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Formins Edit Wikipedia article
|Alt. symbols||LD, FMN|
|Locus||Chr. 15 q13-q14|
|Locus||Chr. 1 q43|
|Formin Homology Region 1|
|Formin Homology 2 Domain|
crystal structures of a formin homology-2 domain reveal a tethered-dimer architecture
|SCOPe||1ux5 / SUPFAM|
|Diaphanous FH3 Domain|
crystal structure of mdia1 gbd-fh3 in complex with rhoc-gmppnp
|DRF Autoregulatory Domain|
crystal structure of the n-terminal mdia1 armadillo repeat region and dimerisation domain in complex with the mdia1 autoregulatory domain (dad)
|Diaphanous GTPase-binding Domain|
crystal structure of mdia1 gbd-fh3 in complex with rhoc-gmppnp
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. Most formins are Rho-GTPase effector proteins. Formins regulate the actin and microtubule cytoskeleton  and are involved in various cellular functions such as cell polarity, cytokinesis, cell migration and SRF transcriptional activity. Formins are multidomain proteins that interact with diverse signalling molecules and cytoskeletal proteins, although some formins have been assigned functions within the nucleus.
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. 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, SH3 (Src homology 3) domain proteins, 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. The FH3 domain is less well conserved and is required for directing formins to the correct intracellular location, such the mitotic spindle, or the projection tip during conjugation. 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. 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.
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.
- Chalkia D, Nikolaidis N, Makalowski W, Klein J, Nei M (December 2008). "Origins and evolution of the formin multigene family that is involved in the formation of actin filaments". Molecular Biology and Evolution. 25 (12): 2717â€“33. doi:10.1093/molbev/msn215. PMC 2721555. PMID 18840602.
- Evangelista M, Zigmond S, Boone C (July 2003). "Formins: signaling effectors for assembly and polarization of actin filaments". Journal of Cell Science. 116 (Pt 13): 2603â€“11. doi:10.1242/jcs.00611. PMID 12775772.
- Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC (June 2015). "The evolution of compositionally and functionally distinct actin filaments". Journal of Cell Science. 128 (11): 2009â€“19. doi:10.1242/jcs.165563. PMID 25788699.
- Goode BL, Eck MJ (2007). "Mechanism and function of formins in the control of actin assembly". Annual Review of Biochemistry. 76: 593â€“627. doi:10.1146/annurev.biochem.75.103004.142647. PMID 17373907.
- Faix J, Grosse R (June 2006). "Staying in shape with formins". Developmental Cell. 10 (6): 693â€“706. doi:10.1016/j.devcel.2006.05.001. PMID 16740473.
- Higgs HN, Peterson KJ (January 2005). "Phylogenetic analysis of the formin homology 2 domain". Molecular Biology of the Cell. 16 (1): 1â€“13. doi:10.1091/mbc.E04-07-0565. PMC 539145. PMID 15509653.
- Kitayama C, Uyeda TQ (February 2003). "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): 711â€“23. doi:10.1242/jcs.00265. PMID 12538772.
- Wallar BJ, Alberts AS (August 2003). "The formins: active scaffolds that remodel the cytoskeleton". Trends in Cell Biology. 13 (8): 435â€“46. doi:10.1016/S0962-8924(03)00153-3. PMID 12888296.
- Uetz P, Fumagalli S, James D, Zeller R (December 1996). "Molecular interaction between limb deformity proteins (formins) and Src family kinases". The Journal of Biological Chemistry. 271 (52): 33525â€“30. doi:10.1074/jbc.271.52.33525. PMID 8969217.
- Takeya R, Sumimoto H (November 2003). "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): 4567â€“75. doi:10.1242/jcs.00769. PMID 14576350.
- Shimada A, Nyitrai M, Vetter IR, KÃ¼hlmann D, Bugyi B, Narumiya S, Geeves MA, Wittinghofer A (February 2004). "The core FH2 domain of diaphanous-related formins is an elongated actin binding protein that inhibits polymerization". Molecular Cell. 13 (4): 511â€“22. doi:10.1016/S1097-2765(04)00059-0. PMID 14992721.
- Kato T, Watanabe N, Morishima Y, Fujita A, Ishizaki T, Narumiya S (February 2001). "Localization of a mammalian homolog of diaphanous, mDia1, to the mitotic spindle in HeLa cells". Journal of Cell Science. 114 (Pt 4): 775â€“84. PMID 11171383.
- Petersen J, Nielsen O, Egel R, Hagan IM (June 1998). "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): 1217â€“28. doi:10.1083/jcb.141.5.1217. PMC 2137179. PMID 9606213.
- Peng J, Wallar BJ, Flanders A, Swiatek PJ, Alberts AS (April 2003). "Disruption of the Diaphanous-related formin Drf1 gene encoding mDia1 reveals a role for Drf3 as an effector for Cdc42". Current Biology. 13 (7): 534â€“45. doi:10.1016/S0960-9822(03)00170-2. PMID 12676083.
- Xu Y, Moseley JB, Sagot I, Poy F, Pellman D, Goode BL, Eck MJ (March 2004). "Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture". Cell. 116 (5): 711â€“23. doi:10.1016/S0092-8674(04)00210-7. PMID 15006353.
- Thompson ME, Heimsath EG, Gauvin TJ, Higgs HN, Kull FJ (January 2013). "FMNL3 FH2-actin structure gives insight into formin-mediated actin nucleation and elongation". Nature Structural & Molecular Biology. 20 (1): 111â€“8. doi:10.1038/nsmb.2462. PMC 3876896. PMID 23222643.
- Palazzo AF, Cook TA, Alberts AS, Gundersen GG (August 2001). "mDia mediates Rho-regulated formation and orientation of stable microtubules". Nature Cell Biology. 3 (8): 723â€“9. doi:10.1038/35087035. PMID 11483957.
- Bartolini F, Gundersen GG (February 2010). "Formins and microtubules". Biochimica et Biophysica Acta. 1803 (2): 164â€“73. doi:10.1016/j.bbamcr.2009.07.006. PMC 2856479. PMID 19631698.
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Formin Homology 2 Domain Provide feedback
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Internal database links
|SCOOP:||DUF1068 DUF1241 EzrA YqgF|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR015425
Formin homology (FH) proteins play a crucial role in the reorganisation of the actin cytoskeleton, which mediates various functions of the cell cortex including motility, adhesion, and cytokinesis [ PUBMED:10631086 ]. Formins are multidomain proteins that interact with diverse signalling molecules and cytoskeletal proteins, although some formins have been assigned functions within the nucleus. Formins are characterised by the presence of three FH domains (FH1, FH2 and FH3), although members of the formin family do not necessarily contain all three domains [ PUBMED:12538772 ]. The proline-rich FH1 domain mediates interactions with a variety of proteins, including the actin-binding protein profilin, SH3 (Src homology 3) domain proteins, and WW domain proteins. The FH2 domain is required for the self-association of formin proteins through the ability of FH2 domains to directly bind each other [ PUBMED:14576350 ], and may also act to inhibit actin polymerisation [ PUBMED:14992721 ]. The FH3 domain ( INTERPRO ) is less well conserved and may be important for determining intracellular localisation of formin family proteins. In addition, some formins can contain a GTPase-binding domain (GBD) ( INTERPRO ) required for binding to Rho small GTPases, and a C-terminal conserved Dia-autoregulatory domain (DAD).
This entry represents the FH2 domain, which was shown by X-ray crystallography to have an elongated, crescent shape containing three helical subdomains [ PUBMED:15006353 ].
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Key: available, not generated, — not available.
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|Seed source:||Alignment kindly provided by SMART|
|Number in seed:||40|
|Number in full:||18054|
|Average length of the domain:||338.00 aa|
|Average identity of full alignment:||25 %|
|Average coverage of the sequence by the domain:||33.17 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||26|
|Download:||download the raw HMM for this family|
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The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the FH2 domain has been found. There are 25 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.