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From Wikipedia, the free encyclopedia
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.[2] Most formins are Rho-GTPase effector proteins. Formins regulate the actin and microtubule cytoskeleton [3][4] and are involved in various cellular functions such as cell polarity, cytokinesis, cell migration and SRF transcriptional activity.[5] Formins are multidomain proteins that interact with diverse signalling molecules and cytoskeletal proteins, although some formins have been assigned functions within the nucleus.
DRF Autoregulatory Domain | |||||||||
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![]() crystal structure of the n-terminal mdia1 armadillo repeat region and dimerisation domain in complex with the mdia1 autoregulatory domain (dad) | |||||||||
Identifiers | |||||||||
Symbol | Drf_DAD | ||||||||
Pfam | PF06345 | ||||||||
InterPro | IPR010465 | ||||||||
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Formins have been found in all eukaryotes studied.[1] In humans, 15 different formin proteins are present that have been classified in 7 subgroups.[6] By contrast, yeasts contain only 2-3 formins.[7]
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.[8][9] 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,[10] SH3 (Src homology 3) domain proteins,[11] and WW domain proteins. The actin nucleation-promoting activity of S. cerevisiae formins has been localized to the FH2 domain.[4] 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.[12][13] 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.[14][15] 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.[16] 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.[16] 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.[17][18]
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.[19][20]