Interaction of the N- and C-terminal Autoregulatory Domains of FRL2 Does Not Inhibit FRL2 Activity

Formin homology proteins are a highly conserved family of cytoskeletal remodeling proteins best known for their ability to induce the formation of long unbranched actin filaments. They accomplish this by nucleating the de novo polymerization of F-actin and also by acting as F-actin barbed end “leaky cappers” that allow filament elongation while antagonizing the function of capping proteins. More recently, it has been reported that the FH2 domains of FRL1 and mDia2 and the plant formin AFH1 are able to bind and bundle actin filaments via distinct mechanisms. We find that like FRL1, FRL2 and FRL3 are also able to bind and bundle actin filaments. In the case of FRL3, this activity is dependent upon a proximal DAD/WH2-like domain that is found C-terminal to the FH2 domain. In addition, we show that, like other Diaphanous-related formins, FRL3 activity is subject to autoregulation mediated by the interaction between its N-terminal DID and C-terminal DAD. In contrast, the DID and DAD of FRL2 also interact in vivo and in vitro but without inhibiting FRL2 activity. These data suggest that current models describing DID/DAD autoregulation via steric hindrance of FH2 activity must be revised. Finally, unlike other formins, we find that the FH2 and N-terminal dimerization domains of FRL2 and FRL3 are able to form hetero-oligomers. Formin homology proteins are a highly conserved family of cytoskeletal remodeling proteins best known for their ability to induce the formation of long unbranched actin filaments. They accomplish this by nucleating the de novo polymerization of F-actin and also by acting as F-actin barbed end “leaky cappers” that allow filament elongation while antagonizing the function of capping proteins. More recently, it has been reported that the FH2 domains of FRL1 and mDia2 and the plant formin AFH1 are able to bind and bundle actin filaments via distinct mechanisms. We find that like FRL1, FRL2 and FRL3 are also able to bind and bundle actin filaments. In the case of FRL3, this activity is dependent upon a proximal DAD/WH2-like domain that is found C-terminal to the FH2 domain. In addition, we show that, like other Diaphanous-related formins, FRL3 activity is subject to autoregulation mediated by the interaction between its N-terminal DID and C-terminal DAD. In contrast, the DID and DAD of FRL2 also interact in vivo and in vitro but without inhibiting FRL2 activity. These data suggest that current models describing DID/DAD autoregulation via steric hindrance of FH2 activity must be revised. Finally, unlike other formins, we find that the FH2 and N-terminal dimerization domains of FRL2 and FRL3 are able to form hetero-oligomers. Formin homology proteins (formins) are a highly conserved family of cytoskeletal regulatory proteins. Over 30 formins have been described to date, with more than 15 family members found in vertebrates (1Higgs H.N. Peterson K.J. Mol. Biol. Cell. 2005; 16: 1-13Crossref PubMed Scopus (209) Google Scholar). Formin activity is required in vivo for a diverse array of cellular functions, such as stress fiber formation, endosome motility, cell motility, cytokinetic ring formation, cell-cell junction assembly, filopodia formation, induction of cell polarity, and activation of the MAL/serum response factor signaling pathway (2Chang F. Drubin D. Nurse P. J. Cell Biol. 1997; 137: 169-182Crossref PubMed Scopus (337) Google Scholar, 3Evangelista M. Pruyne D. Amberg D.C. Boone C. Bretscher A. Nat. Cell Biol. 2002; 4: 260-269Crossref PubMed Google Scholar, 4Feierbach B. Chang F. Curr. Biol. 2001; 11: 1656-1665Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 5Kobielak A. Pasolli H.A. Fuchs E. Nat. Cell Biol. 2004; 6: 21-30Crossref PubMed Scopus (310) Google Scholar, 6Pellegrin S. Mellor H. Curr. 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Cell. 2002; 13: 4088-4099Crossref PubMed Scopus (164) Google Scholar). It is thought that at the core of all of these activities is the ability of formins to regulate actin cytoskeletal dynamics. This is achieved through the activity of two conserved formin homology domains, FH1 and FH2. FH1 consists of proline-rich repeats of varying sizes that can serve as ligands for Src homology 3 and WW domains as well as the small actin-binding protein profilin (14Wallar B.J. Alberts A.S. Trends Cell Biol. 2003; 13: 435-446Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, 15Kovar D.R. Curr. Opin. Cell Biol. 2006; 18: 11-17Crossref PubMed Scopus (197) Google Scholar). FH2 domains form a dimer that induces the polymerization of long, unbranched filaments. It does this by nucleating de novo actin polymerization and by associating with the F-actin barbed end as a “leaky capper,” allowing filament elongation while antagonizing the function of capping proteins (16Romero S. Le Clainche C. Didry D. Egile C. Pantaloni D. Carlier M.F. Cell. 2004; 119: 419-429Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar). However, not all formins nucleate or elongate F-actin with equal potency. For example, mDia1 is an extremely efficient nucleator of polymerization, and its association with the barbed end of actin filaments accelerates elongation (16Romero S. Le Clainche C. Didry D. Egile C. Pantaloni D. Carlier M.F. Cell. 2004; 119: 419-429Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar, 17Kovar D.R. Harris E.S. Mahaffy R. Higgs H.N. Pollard T.D. Cell. 2006; 124: 423-435Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). In contrast, the isolated FH2 domain of FHOD1 does not induce actin polymerization in vivo (18Gasteier J.E. Madrid R. Krautkramer E. Schroder S. Muranyi W. Benichou S. Fackler O.T. J. Biol. Chem. 2003; 278: 38902-38912Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). In addition, FH2 activity may also be influenced by the activity of adjacent domains. For example, in INF2, a WH2 G-actin binding motif antagonizes the nucleation activity of its associated FH2 domain (19Chhabra E.S. Higgs H.N. J. Biol. Chem. 2006; 281: 26754-26767Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). More recently, it has been recognized that the FH2 domains of FRL1, mDia2, and AFH1 are able to bind and bundle actin filaments using at least two distinct mechanisms (20Harris E.S. Rouiller I. Hanein D. Higgs H.N. J. Biol. Chem. 2006; 281: 14383-14392Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 21Michelot A. Derivery E. Paterski-Boujemaa R. Guerin C. Huang S. Parcy F. Staiger C.J. Blanchoin L. Curr. Biol. 2006; 16: 1924-1930Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). The Diaphanous-related formins contain three dimerization interfaces: DID/DAD interactions mediate Diaphanous-related formin autoinhibition, whereas the N-terminal dimerization domain and the C-terminal FH2 each are able to form homodimers. The presence of multiple dimerization domains has called into question previous models that suggest that Diaphanous-related formins in the autoinhibited conformation are monomeric (15Kovar D.R. Curr. Opin. Cell Biol. 2006; 18: 11-17Crossref PubMed Scopus (197) Google Scholar, 22Rose R. Weyand M. Lammers M. Ishizaki T. Ahmadian M.R. Wittinghofer A. Nature. 2005; 435: 513-518Crossref PubMed Scopus (219) Google Scholar, 23Nezami A.G. Poy F. Eck M.J. Structure. 2006; 14: 257-263Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 24Goode, B. L., and Eck, M. J. (2007) Annu. Rev. Biochem.Google Scholar). We reported previously that the dimerization and FH2 domains of mDia1 and mDia2 do not form hetero-oligomeric complexes. We wished to determine the general applicability of this observation to other formins. To this end, we performed an initial structure-function analysis of the highly similar Diaphanous-related formins FRL2 and FRL3 to determine the basic organization of these proteins and test their ability to form hetero-oligomers. As part of this study, we identified two C-terminal WH2/DAD-like motifs in FRL2 and FRL3. The more distal motif is required for FRL3 autoregulation, whereas the more proximal sequence is required for efficient F-actin bundling by both proteins. Moreover, we found that although FRL3 is autoregulated, the highly similar FRL2 is not. Indeed, we find that full-length FRL2 is constitutively active, although its DID is able to bind to its DAD both in vivo and in vitro. Finally, we find that, unlike mDia1 and mDia2, both the FH2 and N-terminal dimerization domains of FRL2 and FRL3 proteins are able to form hetero-oligomers in vivo. Plasmids—The constructs pMLV-LacZ, p3D.A-Luc, and pEF-SRFVP16 were described previously (25Geneste O. Copeland J.W. Treisman R. J. Cell Biol. 2002; 157: 831-838Crossref PubMed Scopus (174) Google Scholar). The constructs f.l.FRL3 FRL3. and of FRL2 with of were by using and as into the and A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (577) Google with and as well as for in Cell were in with and and were in as were at in a with for and for performed as previously described J.W. Copeland Treisman R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, B.J. S. D. Copeland J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were with with and in in were using to the were the in and with with F-actin using at a of proteins were using at a of and proteins were using at a of were at a of and at a of were with a using the a of and proteins by in were performed as previously described J.W. Copeland Treisman R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, B.J. S. D. Copeland J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). response factor response were performed as previously described J.W. Copeland Treisman R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, B.J. S. D. Copeland J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to an in all For and activation in of the is to to allow of the of in vitro actin bundling were performed as previously described (20Harris E.S. Rouiller I. Hanein D. Higgs H.N. J. Biol. Chem. 2006; 281: 14383-14392Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, J.W. Copeland Treisman R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, B.J. S. D. Copeland J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E.S. F. Higgs H.N. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). FRL2 and FRL3 FH2 and N-terminal were in as proteins and F-actin actin to the For actin bundling FH2 and were with F-actin for at were at for at The of to a with of and in of The the were in of of and were to and proteins were by For the with the FH2 for at to the of in vitro actin bundling were performed as previously described J.W. Copeland Treisman R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, B.J. S. D. Copeland J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). FRL2 and were as FH2 were with the of or for at and into a by the of actin for a G-actin of 15 in a has that, sequence the FH2 domains N-terminal dimerization motifs of the formins mDia1 and mDia2 are able to form J.W. Copeland Treisman R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, B.J. S. D. Copeland J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). To test the of this we to the ability of the proteins FRL2 known as and FRL3 known as to form hetero-oligomeric complexes. These proteins homology at the protein their sequence We of FRL2 and FRL3 the full-length the isolated and C-terminal and FH2 domains. These proteins were by in and their and actin stress fiber formation were by and is not of FRL2 to the full-length FH1 and FH2 were by in with F-actin with full-length FRL2 at the cell induces stress fiber formation, and with F-actin in is the have of F-actin of induces stress fiber and of F-actin at the cell that with the protein induces stress of F-actin in at the of the and of actin the of full-length and FH2 of FRL2 induces activation of an activity to activation by of an of FRL2 As of full-length FRL3 not induce F-actin with the presence of well conserved N-terminal DID and C-terminal DAD domains The full-length protein a similar to that with full-length mDia1 B.J. S. D. Copeland J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the FRL3 stress fiber formation The of FRL3 of stress and a of F-actin at the of the The protein in the with at the and with F-actin also stress fiber formation and F-actin in at the of the the protein association with the F-actin in these The were using an This is by the pathway in response to of the cellular of G-actin and as a of the activity of that induce actin polymerization A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar, 12Miralles F. Posern G. Zaromytidou A.I. Treisman R. Cell. 2003; 113: 329-342Abstract Full Text Full Text PDF PubMed Scopus (1084) Google Scholar, 13Copeland J.W. Treisman R. Mol. Biol. Cell. 2002; 13: 4088-4099Crossref PubMed Scopus (164) Google Scholar, O. Copeland J.W. Treisman R. J. Cell Biol. 2002; 157: 831-838Crossref PubMed Scopus (174) Google Scholar, J.W. Copeland Treisman R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, R. Copeland J.W. M. Treisman R. J. 2003; PubMed Scopus Google Scholar, G. A. Treisman R. Mol. Biol. Cell. 2002; 13: PubMed Scopus Google Scholar). As of or the whereas of full-length FRL3 and of N-terminal and FH2 of FRL2 similar as the of FRL3 with the that of full-length FRL2 also in the of stress in These were in the This that, the presence of highly conserved DID and DAD regulatory FRL2 is not subject to To the for the activity of full-length we of the ability of the DID/DAD interaction to be in using isolated and C-terminal in the case of mDia1 and mDia2, the isolated of mDia1 is able to the isolated of mDia2 and a similar we to determine the in FRL2 with the DID or DAD of FRL2 with or in and the actin polymerization were by In both of or to the ability of to induce stress fiber formation and with this a with and activation of also by of or In contrast, of or activity as by and the FRL2 a DID motif that is of inhibiting FRL3 activity in but does not contain a DAD. of the FRL2 and FRL3 C-terminal the presence of two WH2/DAD-like motifs in both proteins To of these motifs is required for the DID we a C-terminal of that the more distal DAD motif The ability of to the activity of this C-terminal by to stress fiber formation and were with these in the of the distal DAD motif of FRL3 a activity as by or in the these we to the more distal motif as DAD and the more proximal motif as WH2 the DAD domain in FRL3, we to determine it is the DAD domain and C-terminal to it in FRL2 that are to DID or it is a general of the FH2 domain of We FRL2 the FRL3 DAD and C-terminal to it and and the ability of to their activity. As to or FH2 activity and it the activity of FRL2 that the DAD domain or and However, unlike the other FRL2 the protein by of or and were with of the full-length FRL2 and FRL3 proteins it is the FRL2 DAD or C-terminal to it that to of FH2 activity. The of FRL2 C-terminal to be by or two the FRL2 DID and DAD domains are to form a or form a that is not to activation of the adjacent FH2 domain. To between these two we to determine the DID and DAD domains of FRL2 are able to interact in vivo. In these we the ability of or to FRL2 and FRL3 C-terminal or the DAD As we found that and were able to in a and we found that and were also able to with a similar as with or and The interaction between and also and the DID and DAD domains of FRL2 are able to interact in but in the case of or this interaction is not that the DID/DAD interaction between the and of FRL2 and FRL3, we similar to the ability of the isolated and full-length proteins to form In to previous with mDia1 and mDia2, we found that we were able to hetero-oligomeric of both the N-terminal dimerization domains and FH2 domains of FRL2 with FRL3 and with these we were also able to hetero-oligomeric of full-length FRL2 with full-length FRL3 FRL2 and FRL3 contain two C-terminal WH2/DAD-like motifs have similar motifs in FH2 activity (19Chhabra E.S. Higgs H.N. J. Biol. Chem. 2006; 281: 26754-26767Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). we FH2 C-terminal with each of these motifs in and the FH2 activity in vivo. of induces the formation of actin stress and actin and the of F-actin in of the distal DAD motif FH2 activity in this of both distal and proximal WH2/DAD-like motifs an of the F-actin and in F-actin We also the function of the using the a of activity as each WH2/DAD-like motif The of these motifs as by and activity in the of the C-terminal DAD activity in vivo. as in of induces stress actin and F-actin to FH2 induces actin and F-actin to of both distal and proximal DAD motifs does not of of and as by activity to activation by of an of of the two WH2/DAD-like motifs of FRL3 a in F-actin also in the FRL2 The protein FRL1 has been to bind and bundle F-actin (20Harris E.S. Rouiller I. Hanein D. Higgs H.N. J. Biol. Chem. 2006; 281: 14383-14392Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, E.S. F. Higgs H.N. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google and actin bundling by the actin-binding protein is dependent its WH2 domain L. B. G. E. A. J. Cell 2006; 119: PubMed Scopus Google Scholar). The proximal WH2/DAD-like motif homology with other WH2 domains we the ability of FRL2 and FRL3 FH2 to bundle actin filaments in vitro. We found that and proteins are able to bundle actin filaments in vitro and In the case of FRL3, of the distal DAD actin bundling and to the proximal WH2/DAD-like motif actin bundling by this protein As we in the of of the WH2/DAD-like motifs activity were In this of the distal DAD F-actin bundling although of the more proximal motif but not F-actin bundling The also able to bundle F-actin in this the proximal WH2/DAD-like motif is a in F-actin bundling than autoregulation, and we the proximal motif as We the F-actin bundling to the interaction between the and C-terminal regulatory domains of FRL2 and FRL3. protein its not induce F-actin bundling in vitro and not of with or the ability of FH2 domain to bundle F-actin and In contrast, with F-actin bundling by However, although of actin to the actin by These were using the polymerization In this both and are able to induce actin of has FRL2 actin polymerization but is able to activity as the case in to but in a We an initial structure-function analysis of the Diaphanous-related formins FRL2 and FRL3. We find that the C-terminal of both FRL2 and FRL3 contain two WH2/DAD-like The more proximal motif we have as homology and of the it in F-actin The more distal motif we have it is required for autoregulation of FRL3. We also show that these proteins are able to form hetero-oligomers through the dimerization of their FH2 or N-terminal domains. F-actin found that both FRL2 and FRL3 are able to bind and to bundle F-actin in vitro. This activity is dependent upon a motif found C-terminal to FH2 and proximal to the regulatory DAD It has been previously that WH2 and DAD domains are similar at the sequence Indeed, the DAD is also a WH2 domain that antagonizes the activity of the FH2 domain (19Chhabra E.S. Higgs H.N. J. Biol. Chem. 2006; 281: 26754-26767Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). The proximal sequence in both FRL2 and FRL3 homology with the WH2 motif found in INF2, and other proteins this sequence also more in that it is required for F-actin bundling by FRL3 and is required for efficient F-actin bundling by This is of the ability of to bind and bundle F-actin in a L. B. G. E. A. J. Cell 2006; 119: PubMed Scopus Google Scholar). In this F-actin bundling is dependent upon G-actin binding by WH2 and the presence of two F-actin binding in L. B. G. E. A. J. Cell 2006; 119: PubMed Scopus Google Scholar). suggest a F-actin bundling by FRL3 is dependent barbed end binding by the FH2 domain and an actin binding the homology between FRL2 and FRL3, the WH2 of F-actin bundling by FRL2 that the two proteins are bundling actin filaments by distinct mechanisms. We a F-actin bundling by FRL2 is to be similar to FRL1 and dependent of the FH2 dimer (20Harris E.S. Rouiller I. Hanein D. Higgs H.N. J. Biol. Chem. 2006; 281: 14383-14392Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, E.S. F. Higgs H.N. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google whereas the F-actin bundling by FRL3 is more similar to F-actin bundling by L. B. G. E. A. J. Cell 2006; 119: PubMed Scopus Google Scholar). is required to determine the WH2 motif found in FRL2 and FRL3 is to F-actin binding into a more analysis of the C-terminal WH2 and DAD motifs of these proteins actin polymerization be reported C. and J. W. in show that full-length FRL2 is constitutively by in This an of the DID and DAD domains to interact or a of this interaction to FH2 activity. in vivo and in vitro we were able to that the DID of FRL2 is able to bind to but this association does not FH2 activity and The of this interaction to FH2 activity a the C-terminal regulatory domain the presence of two motifs in this of suggest that this is not an of is it an of the FH2 domain of the of FRL2 is able to the activity of the FRL3 that FRL2 a DID the C-terminal of FRL2 that contain the DAD of FRL3 are by or in and a full-length FRL2 protein the DAD of FRL3 is autoinhibited and FRL2 FH2 activity can be through a DID/DAD of the DAD of FRL3 with that FRL2 FRL3 autoinhibition, although not to the as of the FRL3 DAD and The observation that, in the of full-length FRL3, the DAD of FRL2 is able to of that the activity of FRL2 in vivo is not to the of regulatory factor in we the that the activity of FRL2 a of a DAD sequence and an FH2 domain that is more to DID/DAD like FRL2 and FRL3, also two C-terminal with the more distal DAD FHOD1 autoregulation A. M. J.E. Fackler O.T. M. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). For FHOD1 and for mDia2, efficient DID/DAD dimerization and is dependent upon a of basic C-terminal to DAD A. M. J.E. Fackler O.T. M. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar, B.J. H.A. Alberts A.S. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). of the FRL2 and FRL3 that the of basic between the of each of these proteins M. J. 2003; Google Scholar). The in this has the least whereas the has the However, we found that the of FRL2 to in a both in vivo and in vitro and it that in this the basic are not required for the DID/DAD interaction as for allowing this interaction to FH2 activity. models suggest that DID and DAD FH2 activity in the autoinhibited conformation by the FH2 domain. However, this be the case for we show that the interaction of DID with the DAD of FRL2 does not FH2 activity. of or not an factor is required to mediate FRL2 in are with a the DID/DAD interaction induces a in the FH2 domain to FH2 activity. for this the of the FH2 domain J. W. Poy F. S. Goode B.L. Eck M.J. J. Mol. Biol. PubMed Scopus Google Scholar). This found the isolated FH2 to be in an autoinhibited the for into DID/DAD of formin activity. we that the DID/DAD interaction is able to mediate of mDia1 and mDia2 B.J. S. D. Copeland J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, we were to of FH2 with FH2 or of the N-terminal dimerization domains the homology by these proteins dimerization domains the FRL2 and FRL3 proteins are highly As with mDia1 and mDia2, we that the DID of FRL2 is able to bind to the DAD of FRL3 and In addition, and unlike mDia1 and mDia2, both the FRL2 and FRL3 N-terminal dimerization domains and FH2 domains are also able to form hetero-oligomers in as the full-length proteins It is not mDia1 and mDia2 or FRL2 and FRL3 the more general for formin protein The ability of FRL2 and FRL3 to form a regulatory for both proteins. a constitutively FRL2 to an autoinhibited FRL3, although the may be FRL3 is to it be of to determine FRL2 and FRL3 in and cell In a for F-actin bundling by formin proteins and suggest that the current of Diaphanous-related formin autoregulation must be revised. We Higgs for of the and members of the for of the with

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