Fifteen formins for an actin filament: A molecular view on the regulation of human formins

Schönichen, André; Geyer, Matthias

doi:10.1016/j.bbamcr.2010.01.014

Cited by 218 publications

(249 citation statements)

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“…Whereas the GBD of mDia1 consists of three ␣-helices (6), this region of human formin homology domain-containing protein 1 (FHOD1) adopts a ubiquitin fold (8). Moreover, other regulatory elements can be present in addition to or as replacements for those mentioned above, such as the PDZ domain in delphilins, the WH2 domain in INF2, and the Spir-binding domain in FMN1 (3,4).…”

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confidence: 99%

“…Besides ForC, Dictyostelium cells contain nine additional formins, most of which convey to the domain organization of vertebrate Diaphanous-related formins (9,11). The mammalian homologue with the most similar domain organization to ForC is human FHOD1 (3).…”

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confidence: 99%

“…Formins are widely expressed multidomain proteins that regulate the spatial and temporal organization of the actin and microtubule cytoskeleton, thereby affecting important cellular functions, such as cytokinesis and cell-cell adhesion (1)(2)(3). The defining element is the ϳ400-amino acid-encompassing "formin homology 2" (FH2) 2 domain that can tightly associate with the barbed end of elongating actin filaments (4).…”

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confidence: 99%

“…The N-terminal "formin homology 3" (FH3) domain mediates interactions with autoinhibitory regulatory elements in the C terminus as well as with other formin regulators. The FH3 domain can be further divided into functional subdomains, such as an armadillo repeat region containing the Diaphanous inhibitory domain (DID) and an ␣-helical dimerization domain (DD) in the Diaphanous-related formin mDia1 (3,6). Binding of the Diaphanous autoinhibitory domain (DAD) to the FH3 domain can inhibit formin function by sterically blocking access of actin to the FH2 region (3,4).…”

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Structure, Dynamics, Lipid Binding, and Physiological Relevance of the Putative GTPase-binding Domain of Dictyostelium Formin C

Dames

Junemann

Sass

et al. 2011

Journal of Biological Chemistry

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Dictyostelium Formin C (ForC) is involved in the regulation of local actin cytoskeleton reorganization (e.g. during cellular adhesion or migration). ForC contains formin homology 2 and 3 (FH2 and -3) domains and an N-terminal putative GTPase-binding domain (GBD) but lacks a canonical FH1 region. To better understand the role of the GBD, its structure, dynamics, lipid-binding properties, and cellular functions were analyzed by NMR and CD spectroscopy and by in vivo fluorescence microscopy. Moreover, the program CS-Rosetta was tested for the structure prediction based on chemical shift data only. The ForC GBD adopts an ubiquitinlike ␣/␤-roll fold with an unusually long loop between ␤-strands 1 and 2. Based on the lipid-binding data, the presence of DPC micelles induces the formation of ␣-helical secondary structure and a rearrangement of the tertiary structure. Lipid-binding studies with a mutant protein and a peptide suggest that the ␤1-␤2 loop is not relevant for these conformational changes. Whereas small amounts of negatively charged phosphoinositides (1,2-dioctanoyl-sn-glycero-3-(phosphoinositol 4,5-bisphosphate) and 1,2-dihexanoyl-sn-glycero-3-(phosphoinositol 3,4,5-trisphosphate)) lower the micelle concentration necessary to induce the observed spectral changes, other negatively charged phospholipids (1,2-dihexanoyl-sn-glycero-3-(phospho-L-serine) and 1,2-dihexanoyl-snglycero-3-phospho-(1 -rac-glycerol)) had no such effect. Interestingly, bicelles and micelles composed of diacylphosphocholines had no effect on the GBD structure. Our data suggest a model in which part of the large positively charged surface area of the GBD mediates localization to specific membrane patches, thereby regulating interactions with signaling proteins. Our cellular localization studies show that both the GBD and the FH3 domain are required for ForC targeting to cell-cell contacts and early phagocytic cups and macropinosomes.Formins are widely expressed multidomain proteins that regulate the spatial and temporal organization of the actin and microtubule cytoskeleton, thereby affecting important cellular functions, such as cytokinesis and cell-cell adhesion (1-3). The defining element is the ϳ400-amino acid-encompassing "formin homology 2" (FH2) 2 domain that can tightly associate with the barbed end of elongating actin filaments (4). In nearly all formins, the FH2 domain is preceded by a prolinerich "formin homology 1" (FH1) region that varies in length and the number of binding sites for profilin and that is used to recruit profilin-actin complexes for filament elongation. The influence of the FH2 domain on the rate of filament elongation depends on the length and composition of the FH1 region and the connecting linker (2, 4, 5). Most formins contain additional regulatory domains. The N-terminal "formin homology 3" (FH3) domain mediates interactions with autoinhibitory regulatory elements in the C terminus as well as with other formin regulators. The FH3 domain can be further divided into functional subdomains, such as an armadill...

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Structure, Dynamics, Lipid Binding, and Physiological Relevance of the Putative GTPase-binding Domain of Dictyostelium Formin C

Dames

Junemann

Sass

et al. 2011

Journal of Biological Chemistry

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“…Rho binds to the formin N-terminal GTPase-binding domains (GBDs) and causes the adjacent Dia-inhibitory domain (DID) to release the C-terminal Dia-autoregulatory domain (DAD) that flanks the FH2 domain. This release allows the FH2 domain to nucleate actin (Schonichen and Geyer, 2010;Wallar et al, 2006). All apicomplexan parasites lack these regulatory domains, but there is abundant literature covering studies in mammals and yeast that highlight how phosphorylation regulates formins activity (Cheng et al, 2011;Iskratsch et al, 2010;Wang et al, 2009).…”

Section: Actin Dynamicsmentioning

confidence: 99%

Does protein phosphorylation govern host cell entry and egress by the Apicomplexa?

Jacot

Soldati‐Favre

2012

International Journal of Medical Microbiology

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a b s t r a c tMembers of the phylum Apicomplexa are responsible for a wide range of diseases in humans and animals. The absence of an effective vaccine or safe curing drugs and the continuous emergence of resistant parasites to available treatments impose a high demand on the identification of novel targets for intervention against the apicomplexans. Protein kinases are considered attractive potential therapeutic targets not only against cancers but also to combat infectious diseases. The scope and aim of this review is to report on the recent progress in dissecting the impact of protein phosphorylation in regulating motility and invasion.

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The Formin FHOD1 in Cardiomyocytes

Dwyer

Pluess

Iskratsch

et al. 2014

The Anatomical Record

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Members of the formin family are known to be involved in the regulation of the actin cytoskeleton. We have recently identified a muscle specific splice variant of the formin FHOD3 and demonstrated its role in the maintenance of the contractile filaments of cardiomyocytes. Here, we characterize the expression and subcellular localization of FHOD3's closest relative, FHOD1, in the heart. Confocal microscopy shows that FHOD1 is mainly located at the intercalated disc, the special type of cell-cell contact between cardiomyocytes, but also partially associated with the myofibrils. Subcellular targeting of FHOD1 is probably mediated by its N-terminal domain, since expression constructs lacking this domain show aberrant localization in primary cultures of neonatal rat cardiomyocytes. Finally, we show that in contrast to FHOD3, FHOD1 shows increased expression levels in dilated cardiomyopathy, suggesting that the two formins play distinct roles and are differentially regulated in cardiomyocytes. Anat Rec, 297:1560Rec, 297: -1570Rec, 297: , 2014. V C 2014 Wiley Periodicals, Inc.Key words: formin; actin; intercalated disc; sarcomere Cardiomyocytes, which make up the bulk of heart mass, are characterized by an exquisitely organized cytoskeleton, which is the basis of maximal functional output (Ehler, 2010). The actin cytoskeleton comprises the thin filaments in the myofibrils, which mediate muscle contraction together with the thick (myosin) filaments, but in addition plays also a role in the organization of the plasma membrane cytoskeleton as well as in the anchoring of myofibrils at the specialized type of cell-cell contact in heart tissue, the intercalated disc (Dwyer et al., 2012). Despite this crucial role of actin in the function of cardiomyocytes, it is subjected to an impressive amount of protein turnover. Measurements in rat hearts have suggested that actin has a half-life of about 10 days (Martin, 1981). How the exchange of actin molecules is achieved in the continuously working cardiomyocyte is not well understood.We have recently focused our attention on a potential role of formins in the heart. Formins are proteins, which are mainly involved in the formation of linear actin filaments (Chesarone et al., 2010). They are characterized by the possession of an FH1 and an FH2 domain (for domain layout of formins see Fig. 1), which together make up the actin capturing and polymerization machinery and so far 15 different formins were described in mammals (Sch€ onichen and Geyer, 2010).One characteristic of formins is that they normally exist in an autoinhibited state, which is brought about Abbreviations used: DAD 5 Diaphanous autoregulatory domain; DCM 5 dilated cardiomyopathy; DID 5 Diaphanous inhibitory domain; FH 5 formin homology domain; GBD 5 GTPase binding domain; NRC 5 neonatal rat cardiomyocytes.

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Fifteen formins for an actin filament: A molecular view on the regulation of human formins

Cited by 218 publications

References 123 publications

Structure, Dynamics, Lipid Binding, and Physiological Relevance of the Putative GTPase-binding Domain of Dictyostelium Formin C

Structure, Dynamics, Lipid Binding, and Physiological Relevance of the Putative GTPase-binding Domain of Dictyostelium Formin C

Does protein phosphorylation govern host cell entry and egress by the Apicomplexa?

The Formin FHOD1 in Cardiomyocytes

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