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]
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.[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 proteinprofilin,[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-terminalconserved 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
mammaliancells 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.
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]
^Wallar BJ, Alberts AS (August 2003). "The formins: active scaffolds that remodel the cytoskeleton". Trends in Cell Biology. 13 (8): 435–46.
doi:
10.1016/S0962-8924(03)00153-3.
PMID12888296.
^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): 775–84.
doi:
10.1242/jcs.114.4.775.
hdl:2433/150544.
PMID11171383.
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]
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.[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 proteinprofilin,[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-terminalconserved 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
mammaliancells 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.
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]
^Wallar BJ, Alberts AS (August 2003). "The formins: active scaffolds that remodel the cytoskeleton". Trends in Cell Biology. 13 (8): 435–46.
doi:
10.1016/S0962-8924(03)00153-3.
PMID12888296.
^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): 775–84.
doi:
10.1242/jcs.114.4.775.
hdl:2433/150544.
PMID11171383.