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• W2019933251 abstract "The cofilins are members of a protein family that binds monomeric and filamentous actin, severs actin filaments, and increases monomer off-rate from the pointed end. Here, we characterize the cofilin-actin interface. We confirm earlier work suggesting the importance of the lower region of subdomain 1 encompassing the N and C termini (site 1) in cofilin binding. In addition, we report the discovery of a new cofilin binding site (site 2) from residues 112–125 that form a helix toward the upper, rear surface of subdomain 1 in the standard actin orientation (Kabsch, W., Mannherz, H. G., Suck, D., Pai, E. F., and Holmes, K. C. (1990) Nature 347, 37–44). We propose that cofilin binds “behind” one monomer and “in front” of the other longitudinally associated monomer, accounting for the fact that cofilin alters the twist in the actin (McGough, A., Pope, B., Chiu, W., and Weeds, A. (1997) J. Cell Biol. 138, 771–781). The characterization of the cofilin-actin interface will facilitate an understanding of how cofilin severs and depolymerizes filaments and may shed light on the mechanism of the gelsolin family because they share a similar fold with the cofilins (Hatanaka, H., Ogura, K., Moriyama, K., Ichikawa, S., Yahara, I., and Inagiki, F. (1996) Cell 85, 1047–1055). The cofilins are members of a protein family that binds monomeric and filamentous actin, severs actin filaments, and increases monomer off-rate from the pointed end. Here, we characterize the cofilin-actin interface. We confirm earlier work suggesting the importance of the lower region of subdomain 1 encompassing the N and C termini (site 1) in cofilin binding. In addition, we report the discovery of a new cofilin binding site (site 2) from residues 112–125 that form a helix toward the upper, rear surface of subdomain 1 in the standard actin orientation (Kabsch, W., Mannherz, H. G., Suck, D., Pai, E. F., and Holmes, K. C. (1990) Nature 347, 37–44). We propose that cofilin binds “behind” one monomer and “in front” of the other longitudinally associated monomer, accounting for the fact that cofilin alters the twist in the actin (McGough, A., Pope, B., Chiu, W., and Weeds, A. (1997) J. Cell Biol. 138, 771–781). The characterization of the cofilin-actin interface will facilitate an understanding of how cofilin severs and depolymerizes filaments and may shed light on the mechanism of the gelsolin family because they share a similar fold with the cofilins (Hatanaka, H., Ogura, K., Moriyama, K., Ichikawa, S., Yahara, I., and Inagiki, F. (1996) Cell 85, 1047–1055). actin depolymerizing factor trifluoroethanol N-iodoacetyl-N′-(5 sulfo-1-naphthyl)ethylenediamine enzyme-linked immunosorbent assay actin-binding protein monomeric actin filamentous actin gelsolin segment G Many motile processes in cells require cyclic polymerization and depolymerization of actin filaments. In cell locomotion for example, actin is polymerized at the leading edge of the cell and is recycled by depolymerizing toward the cell center. The rate constants of pure actin have been established (1Pollard T.D. J. Cell Biol. 1986; 103: 2747-2754Crossref PubMed Scopus (584) Google Scholar), and it is clear that a discrepancy exists between these known rates and those calculated from filament turnover in cells (2Theriot J.A. Mitchison T.J. Trends Cell Biol. 1992; 2: 219-222Abstract Full Text PDF PubMed Scopus (52) Google Scholar). A host of actin-binding proteins are known that dramatically alter the behavior of actin in vitro, and of these, the cofilins have been suggested to have the correct properties to increase filament turnover in cells (3Maciver S.K. Weeds A.G. FEBS Lett. 1994; 347: 251-256Crossref PubMed Scopus (96) Google Scholar). This view has been confirmed by studies with living Saccharomyces (4Lappalainen P. Drubin D.G. Nature. 1997; 388: 78-82Crossref PubMed Scopus (363) Google Scholar) andDictyostelium (5Aizawa H. Sutoh K. Yahara I. J. Cell Biol. 1996; 132: 335-344Crossref PubMed Scopus (129) Google Scholar) and by Listeria motility assays (6Carlier M.-F. Laurent V. Santolini J. Melki R. Didry D. Xia G.-X. Hong Y. Chua N.-H. Pantaloni D. J. Cell Biol. 1997; 136: 1307-1323Crossref PubMed Scopus (820) Google Scholar, 7Rosenblatt J. Agnew B.J. Abe H. Bamburg J.R. Mitchison T.J. J. Cell Biol. 1997; 136: 1323-1332Crossref PubMed Scopus (190) Google Scholar).The cofilins are a group of low molecular mass (15–21 kDa), actin-binding proteins that depolymerize actin filaments (8Moon A. Drubin D.G. Mol. Biol. Cell. 1995; 6: 1423-1431Crossref PubMed Scopus (226) Google Scholar). This group includes vertebrate cofilin (9Nishida E. Maekawa S. Sakai H. Biochemistry. 1984; 23: 5307-5313Crossref PubMed Scopus (249) Google Scholar) and ADF1 (10Bamburg J.R. Harris H.E. Weeds A.G. FEBS Lett. 1980; 121: 178-182Crossref PubMed Scopus (158) Google Scholar), twinstar fromDrosophila (11Gunsalus K.C. Bonaccorsi S. Williams E. Verni F. Gatti M. Goldberg M.L. J. Cell Biol. 1995; 97: 1259-1263Google Scholar), depactin from echinoderms (12Mabuchi I. J. Cell Biol. 1983; 97: 1612-1621Crossref PubMed Scopus (100) Google Scholar), ADFs from plants (13Lopez I. Anthony R.G. Maciver S.K. Jiang C.-J. Khan S. Weeds A.G. Hussey P.J. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7415-7420Crossref PubMed Scopus (108) Google Scholar), Unc-60 from nematode (14McKim K.S. Matheson C. Marra M.A. Wakarchuk M.F. Baillie D.L. Mol. Gen. Genet. 1994; 242: 346-357Crossref PubMed Scopus (100) Google Scholar), cofilins fromSaccharomyces (15Moon A.L. Janmey P.A. Louie K.A. Drubin D.G. J. Cell Biol. 1993; 120: 421-435Crossref PubMed Scopus (201) Google Scholar, 16Iida K. Moriyama K. Matsumoto S. Kawasaki H. Nishida E. Yahara I. Gene. 1993; 124: 115-120Crossref PubMed Scopus (123) Google Scholar) and Dictyostelium (17Aizawa H. Sutoh K. Tsubuki S. Kawashima S. Ishii A. Yahara I. J. Biol. Chem. 1995; 270: 10923-10932Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), and actophorin from Acanthamoeba castellanii (18Cooper J.A. Blum J.D. Williamson Jr., R.C. Pollard T.D. J. Biol. Chem. 1986; 261: 477-485Abstract Full Text PDF PubMed Google Scholar).The mechanism by which cofilin depolymerizes actin filament has been contentious. Soon after the discovery of the first member of the family (10Bamburg J.R. Harris H.E. Weeds A.G. FEBS Lett. 1980; 121: 178-182Crossref PubMed Scopus (158) Google Scholar), several authors suggested that depolymerization occurred through severing (9Nishida E. Maekawa S. Sakai H. Biochemistry. 1984; 23: 5307-5313Crossref PubMed Scopus (249) Google Scholar, 18Cooper J.A. Blum J.D. Williamson Jr., R.C. Pollard T.D. J. Biol. Chem. 1986; 261: 477-485Abstract Full Text PDF PubMed Google Scholar). Evidence for a severing mechanism later came from videomicroscopy (19Maciver S.K. Zot H.G. Pollard T.D. J. Cell Biol. 1991; 115: 1611-1620Crossref PubMed Scopus (193) Google Scholar, 20Hawkins M. Pope B. Maciver S.K. Weeds A.G. Biochemistry. 1993; 32: 9985-9993Crossref PubMed Scopus (239) Google Scholar), but this was later challenged (6Carlier M.-F. Laurent V. Santolini J. Melki R. Didry D. Xia G.-X. Hong Y. Chua N.-H. Pantaloni D. J. Cell Biol. 1997; 136: 1307-1323Crossref PubMed Scopus (820) Google Scholar) as it was shown (6Carlier M.-F. Laurent V. Santolini J. Melki R. Didry D. Xia G.-X. Hong Y. Chua N.-H. Pantaloni D. J. Cell Biol. 1997; 136: 1307-1323Crossref PubMed Scopus (820) Google Scholar, 21Maciver S.K. Pope B.J. Whytock S. Weeds A.G. Eur. J. Biochem. 1998; 256: 388-397Crossref PubMed Scopus (116) Google Scholar) that cofilins increased the off-rate from the pointed end of the filament. However, the two opinions are not necessarily exclusive (22Theriot J.A. J. Cell Biol. 1997; 136: 1165-1168Crossref PubMed Scopus (138) Google Scholar, 23Maciver S.K. Curr. Opin. Cell Biol. 1998; 10: 140-144Crossref PubMed Scopus (94) Google Scholar, 24Blanchoin L. Pollard T.D. J. Biol. Chem. 1998; 273: 25106-25111Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar), and a similar mechanism has been proposed for both events (23Maciver S.K. Curr. Opin. Cell Biol. 1998; 10: 140-144Crossref PubMed Scopus (94) Google Scholar). We report the identification of a cofilin-actin interface that is compatible with the observation that cofilin increases the twist in the actin filament (25McGough A. Pope B. Chiu W. Weeds A. J. Cell Biol. 1997; 138: 771-781Crossref PubMed Scopus (572) Google Scholar) but does not fit the model presented by these authors. We propose that some of the density attributed to cofilin (25McGough A. Pope B. Chiu W. Weeds A. J. Cell Biol. 1997; 138: 771-781Crossref PubMed Scopus (572) Google Scholar) is actually the bulk of subdomain 2 of actin pushed forward by cofilin. Cofilin lies behind subdomain 2 of one monomer and in front of subdomain 1 of the longitudinally associated monomer, immediately toward the pointed end of the filament.Our model may also be applicable to the many other ABPs that contain regions homologous to cofilins that bind to actin (reviewed in Ref. 26Lappalainen P. Kessels M.M. Cope J.T.V. Drubin D.G. Mol. Biol. Cell. 1998; 9: 1951-1959Crossref PubMed Scopus (160) Google Scholar) and to the gelsolin-villin family of ABPs because the gelsolin fold (27McLaughlin P.J. Gooch J.T. Mannherz H.G. Weeds A.G. Nature. 1993; 364: 685-692Crossref PubMed Scopus (493) Google Scholar, 28Burtnick L.D. Koepf E.K. Grimes J. Jones E.Y. Stuart D.I. McLaughlin P.J. Robinson R.C. Cell. 1997; 90: 661-670Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar) is similar to that of the ADF-cofilin fold (29Hatanaka H. Ogura K. Moriyama K. Ichikawa S. Yahara I. Inagiki F. Cell. 1996; 85: 1047-1055Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar).DISCUSSIONADF-cofilins are remarkable in that they alter the filament twist of F-actin (25McGough A. Pope B. Chiu W. Weeds A. J. Cell Biol. 1997; 138: 771-781Crossref PubMed Scopus (572) Google Scholar). Nishida et al. (9Nishida E. Maekawa S. Sakai H. Biochemistry. 1984; 23: 5307-5313Crossref PubMed Scopus (249) Google Scholar) had commented that the structure of cofilin-bound filaments was possibly different from that of F-actin alone and noted that the spectra of cofilin-decorated, pyrene-labeled F-actin was similar to that of G-actin. Our model (Fig.9) explains this. The presence of cofilin pushes the DNase 1 loop from one actin monomer away from the C terminus of the monomer below thus removing that environment afforded by the DNase 1 loop that causes the large change in pyrene fluorescence normally associated with actin polymerization (53Kouyama T. Mihashi K. Eur. J. Biochem. 1981; 114: 33-38Crossref PubMed Scopus (718) Google Scholar). The model proposes that cofilin makes contact with two longitudinally associated actin monomers within the filament, through two sites on cofilin (site 1 and site 2). Site 1 is centered on the N terminus and Lys112and Lys114 (human ADF and cofilin) at the start of the third helix (α3) and makes contact with the lower part of actin's subdomain 1. Site 2 is centered on the last helix of cofilin (α4), which we propose makes contact with the 112–125 helix of actin identified as a cofilin binding site in this study. Whereas the region 112–125 is α-helical in the parent actin molecule (27McLaughlin P.J. Gooch J.T. Mannherz H.G. Weeds A.G. Nature. 1993; 364: 685-692Crossref PubMed Scopus (493) Google Scholar, 52Kabsch W. Mannherz H.G. Suck D. Pai E.F. Holmes K.C. Nature. 1990; 347: 37-44Crossref PubMed Scopus (1522) Google Scholar), we have found that this peptide in solution is in a predominantly non-helical state (Fig. 5). It is known that the helical conformation can be selectively stabilized in the presence of TFE, and we have shown by this agent that 112–125 maintains a propensity to adopt an α-helical conformation in solution. Cofilin binds this peptide, but we do not know if in doing so cofilin stabilizes the α-helical state or induces the α-helical state prior to binding. However, in previous work we demonstrated that the binding of the unfolded peptide, thymosin β4, was enhanced in the presence of TFE (54Feinberg J. Heitz F. Benyamin Y. Roustan C. Biochem. Biophys. Res. Commun. 1996; 222: 127-132Crossref PubMed Scopus (17) Google Scholar). This model is quite different from that suggested by McGough et al. (25McGough A. Pope B. Chiu W. Weeds A. J. Cell Biol. 1997; 138: 771-781Crossref PubMed Scopus (572) Google Scholar), who placed cofilin “in front” of subdomain 2 of actin in the standard orientation. It is difficult to imagine how such an orientation could result in the change in twist of the actin filament observed, rather this orientation may be expected to alter the twist in the opposite direction. Our model, in which cofilin opens up the interface between the longitudinally associated actin subunits by intercalating between them (Fig. 9), produces the change in filament twist by increasing the angle of rotation between each longitudinally associated actin. The high degree of cooperation evident in the binding of ADF-cofilins to F-actin (20Hawkins M. Pope B. Maciver S.K. Weeds A.G. Biochemistry. 1993; 32: 9985-9993Crossref PubMed Scopus (239) Google Scholar, 21Maciver S.K. Pope B.J. Whytock S. Weeds A.G. Eur. J. Biochem. 1998; 256: 388-397Crossref PubMed Scopus (116) Google Scholar, 25McGough A. Pope B. Chiu W. Weeds A. J. Cell Biol. 1997; 138: 771-781Crossref PubMed Scopus (572) Google Scholar) has been explained by the changed twist they induce in the filament (25McGough A. Pope B. Chiu W. Weeds A. J. Cell Biol. 1997; 138: 771-781Crossref PubMed Scopus (572) Google Scholar). We propose that in opening up a space between two subunits at one side of the filament, this also places a strain on the opposite longitudinally associated pair of actin subunits across (and along) the filament, allowing another cofilin to bind along the axis of the filament. McGough et al. (25McGough A. Pope B. Chiu W. Weeds A. J. Cell Biol. 1997; 138: 771-781Crossref PubMed Scopus (572) Google Scholar) have suggested that histidines 40, 87, 88, and 101 on the actin surface may contribute to the pH sensitivity of the ADF-cofilins. Our model also suggests that these histidines are likely to be close to the interface between ADF-cofilin and the actin subunits. However, the actin structure in part of this region is disordered (27McLaughlin P.J. Gooch J.T. Mannherz H.G. Weeds A.G. Nature. 1993; 364: 685-692Crossref PubMed Scopus (493) Google Scholar) or constricted (52Kabsch W. Mannherz H.G. Suck D. Pai E.F. Holmes K.C. Nature. 1990; 347: 37-44Crossref PubMed Scopus (1522) Google Scholar) in the available actin structures, making predictions premature.The cofilin-actin interface has been investigated by a number of methods including chemical cross-linking (19Maciver S.K. Zot H.G. Pollard T.D. J. Cell Biol. 1991; 115: 1611-1620Crossref PubMed Scopus (193) Google Scholar, 55Sutoh K. Mabuchi I. Biochemistry. 1984; 23: 6757-6761Crossref Scopus (33) Google Scholar, 56Sutoh K. Mabuchi I. Biochemistry. 1989; 28: 102-106Crossref PubMed Scopus (35) Google Scholar, 57Muneyuki E. Nishida E. Sutoh K. Sakai H. J. Biochem. ( Tokyo ). 1985; 97: 568-573Google Scholar, 58Giuliano K.A. Khatib F.A. Hayden S.M. Daoud E.W.R. Adams M.E. Amorese D.A. Bernstein B.W. Bamburg J.R. Biochemistry. 1988; 27: 8931-8938Crossref PubMed Scopus (43) Google Scholar), competition with other ABPs (24Blanchoin L. Pollard T.D. J. Biol. Chem. 1998; 273: 25106-25111Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 59Bernstein B.W. Bamburg J.R. Cell Motil. 1982; 2: 1-8Crossref PubMed Scopus (203) Google Scholar, 60Yonezawa N. Nishida E. Maekawa S. Sakai H. Biochem. J. 1988; 251: 121-127Crossref PubMed Scopus (38) Google Scholar, 61Pope B. Way M. Matsudaira P.T. Weeds A.G. FEBS Lett. 1994; 338: 58-62Crossref PubMed Scopus (62) Google Scholar, 62Van Troys M. Dewitte D. Verschelde J.-L. Goethals M. Vanderkerckhove J. Ampe C. J. Biol. Chem. 1997; 272: 32750-32758Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 63Wriggers W. Tang J.X. Azuma T. Marks P.W. Janmey P.A. J. Mol. Biol. 1998; 282: 921-932Crossref PubMed Scopus (55) Google Scholar), structural prediction analysis (63Wriggers W. Tang J.X. Azuma T. Marks P.W. Janmey P.A. J. Mol. Biol. 1998; 282: 921-932Crossref PubMed Scopus (55) Google Scholar), and mutagenesis (64Jiang C.-J. Weeds A.G. Khan S. Hussey P.J. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9973-9978Crossref PubMed Scopus (45) Google Scholar, 65Lappalainen P. Fedorov E.V. Fedorov A.A. Almo S.C Drubin D.G. EMBO J. 1997; 16: 5520-5530Crossref PubMed Scopus (209) Google Scholar). The consensus of these studies is that subdomain 1 of actin is the principal actin-binding interface that binds the long helix of the ADF-cofilin. However, this remains a contentious area, especially on this second point.Chemical cross-linking studies indicate that the N and C termini of actin interact with depactin (55Sutoh K. Mabuchi I. Biochemistry. 1984; 23: 6757-6761Crossref Scopus (33) Google Scholar) and that the N terminus of depactin contains an actin binding site (56Sutoh K. Mabuchi I. Biochemistry. 1989; 28: 102-106Crossref PubMed Scopus (35) Google Scholar). Subdomain 1 of actin was also implicated in the binding of Acanthamoeba actophorin to G-actin as actophorin competes for cross-linking (19Maciver S.K. Zot H.G. Pollard T.D. J. Cell Biol. 1991; 115: 1611-1620Crossref PubMed Scopus (193) Google Scholar) and binding (24Blanchoin L. Pollard T.D. J. Biol. Chem. 1998; 273: 25106-25111Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar) with profilin. Profilin is known to be cross-linked to glutamic acid 364 of actin (48Vanderkerckhove J.S. Kaiser D.A. Pollard T.D. J. Cell Biol. 1989; 109: 619-626Crossref PubMed Scopus (86) Google Scholar). Cofilin can be cross-linked to residues 1–12 on actin (58Giuliano K.A. Khatib F.A. Hayden S.M. Daoud E.W.R. Adams M.E. Amorese D.A. Bernstein B.W. Bamburg J.R. Biochemistry. 1988; 27: 8931-8938Crossref PubMed Scopus (43) Google Scholar), and ADF can be cross-linked to cysteine 374 on actin (58Giuliano K.A. Khatib F.A. Hayden S.M. Daoud E.W.R. Adams M.E. Amorese D.A. Bernstein B.W. Bamburg J.R. Biochemistry. 1988; 27: 8931-8938Crossref PubMed Scopus (43) Google Scholar). Also many have found that various fluorescent labels on cysteine 374 are quenched by ADF-cofilin binding (6Carlier M.-F. Laurent V. Santolini J. Melki R. Didry D. Xia G.-X. Hong Y. Chua N.-H. Pantaloni D. J. Cell Biol. 1997; 136: 1307-1323Crossref PubMed Scopus (820) Google Scholar, 9Nishida E. Maekawa S. Sakai H. Biochemistry. 1984; 23: 5307-5313Crossref PubMed Scopus (249) Google Scholar, 15Moon A.L. Janmey P.A. Louie K.A. Drubin D.G. J. Cell Biol. 1993; 120: 421-435Crossref PubMed Scopus (201) Google Scholar, 21Maciver S.K. Pope B.J. Whytock S. Weeds A.G. Eur. J. Biochem. 1998; 256: 388-397Crossref PubMed Scopus (116) Google Scholar, 24Blanchoin L. Pollard T.D. J. Biol. Chem. 1998; 273: 25106-25111Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 66Zechel K. Biochemistry. 1993; 290: 411-417Crossref Scopus (12) Google Scholar).The position of the actin binding site of ADF-cofilins on actin gained by competition with other ABPs and reagents has produced some contrary evidence. It is known that ADF-cofilin binding is inhibited by phalloidin (6Carlier M.-F. Laurent V. Santolini J. Melki R. Didry D. Xia G.-X. Hong Y. Chua N.-H. Pantaloni D. J. Cell Biol. 1997; 136: 1307-1323Crossref PubMed Scopus (820) Google Scholar, 19Maciver S.K. Zot H.G. Pollard T.D. J. Cell Biol. 1991; 115: 1611-1620Crossref PubMed Scopus (193) Google Scholar, 60Yonezawa N. Nishida E. Maekawa S. Sakai H. Biochem. J. 1988; 251: 121-127Crossref PubMed Scopus (38) Google Scholar). Tropomyosin is known to compete with ADF for F-actin binding (9Nishida E. Maekawa S. Sakai H. Biochemistry. 1984; 23: 5307-5313Crossref PubMed Scopus (249) Google Scholar, 60Yonezawa N. Nishida E. Maekawa S. Sakai H. Biochem. J. 1988; 251: 121-127Crossref PubMed Scopus (38) Google Scholar). It is tempting to speculate therefore that the tropomyosin and ADF binding sites overlap to some extent; however, it is known that the tropomyosin site is some distance from those of ADF-cofilins (reviewed in Ref. 67Sheterline P. Clayton J. Sparrow J. Prot. Profile. 1995; 2: 58-59Google Scholar). Tropomyosin increases the regularity of the helical twist in actin (68Stokes D.L. DeRosier D.J. J. Cell Biol. 1987; 104: 1005-1017Crossref PubMed Scopus (64) Google Scholar) but does not vary it as ADF-cofilin does (25McGough A. Pope B. Chiu W. Weeds A. J. Cell Biol. 1997; 138: 771-781Crossref PubMed Scopus (572) Google Scholar). It is likely that the twist induced by ADF is not compatible with binding by tropomyosin at its distant site, explaining the apparent competition for binding. The same explanation is very likely for phalloidin. Phalloidin binds F-actin extremely tightly, yet ADF-cofilin competes for binding (60Yonezawa N. Nishida E. Maekawa S. Sakai H. Biochem. J. 1988; 251: 121-127Crossref PubMed Scopus (38) Google Scholar). Myosin, which binds to the subdomain 1, including fragment 96–132 on actin (50Labbe J.P. Boyer M. Méjean C. Roustan C. Benyamin Y. Eur. J. Biochem. 1993; 215: 17-24Crossref PubMed Scopus (16) Google Scholar), competes for actin binding with ADF-cofilin (9Nishida E. Maekawa S. Sakai H. Biochemistry. 1984; 23: 5307-5313Crossref PubMed Scopus (249) Google Scholar), in agreement with our model. The so called “headpiece” of villin also competes with ADF for binding to actin (61Pope B. Way M. Matsudaira P.T. Weeds A.G. FEBS Lett. 1994; 338: 58-62Crossref PubMed Scopus (62) Google Scholar), but only partial and weak competition was evident between α-actinin and cofilin (60Yonezawa N. Nishida E. Maekawa S. Sakai H. Biochem. J. 1988; 251: 121-127Crossref PubMed Scopus (38) Google Scholar).The structures of three cofilins, ADF (29Hatanaka H. Ogura K. Moriyama K. Ichikawa S. Yahara I. Inagiki F. Cell. 1996; 85: 1047-1055Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar), yeast cofilin (69Fedorov A. Lappalainen P. Fedorov E.V. Drubin D.G. Almo S.C. Nat. Struct. Biol. 1997; 4: 366-369Crossref PubMed Scopus (94) Google Scholar), and actophorin (70Leonard S. Gittis A. Petrella E. Pollard T. Lattman E. Nat. Struct. Biol. 1997; 4: 369-373Crossref PubMed Scopus (61) Google Scholar), have been determined. Interestingly, cofilins have an overall fold similar to the gelsolin segment 1 (G1) (27McLaughlin P.J. Gooch J.T. Mannherz H.G. Weeds A.G. Nature. 1993; 364: 685-692Crossref PubMed Scopus (493) Google Scholar), leading some others (29Hatanaka H. Ogura K. Moriyama K. Ichikawa S. Yahara I. Inagiki F. Cell. 1996; 85: 1047-1055Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 63Wriggers W. Tang J.X. Azuma T. Marks P.W. Janmey P.A. J. Mol. Biol. 1998; 282: 921-932Crossref PubMed Scopus (55) Google Scholar) to suggest that ADF-cofilin binds actin in a similar manner as G1. Gelsolin is a calcium-sensitive actin-binding, severing, and nucleating protein that is composed of six similar domains (G1–6) (71Weeds A. Maciver S. Curr. Opin. Cell Biol. 1993; 5: 63-69Crossref PubMed Scopus (148) Google Scholar). Although the six domains are similar in both sequence and structure (28Burtnick L.D. Koepf E.K. Grimes J. Jones E.Y. Stuart D.I. McLaughlin P.J. Robinson R.C. Cell. 1997; 90: 661-670Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar), it is known that whereas G1 and G4 bind a similar site on actin (72Pope B. Way M. Weeds A.G. FEBS Lett. 1991; 280: 70-74Crossref PubMed Scopus (59) Google Scholar, 73Pope B. Maciver S. Weeds A. Biochemistry. 1995; 34: 1583-1588Crossref PubMed Scopus (65) Google Scholar), G2 binds F-actin alone. G2 is thought to bind actin in the region of the outer surfaces of subdomains 1 and 2 (62Van Troys M. Dewitte D. Verschelde J.-L. Goethals M. Vanderkerckhove J. Ampe C. J. Biol. Chem. 1997; 272: 32750-32758Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). In support of this contention, G2–3 competes with cofilin for actin binding (62Van Troys M. Dewitte D. Verschelde J.-L. Goethals M. Vanderkerckhove J. Ampe C. J. Biol. Chem. 1997; 272: 32750-32758Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar), however it is also known that G1 also competes with cofilin for actin binding (63Wriggers W. Tang J.X. Azuma T. Marks P.W. Janmey P.A. J. Mol. Biol. 1998; 282: 921-932Crossref PubMed Scopus (55) Google Scholar). These apparently disparate findings are compatible with our model (Fig. 9). Stable F-actin binding can only take place at low pH values where cofilin binds actin monomers within the filament via site 1 and site 2. These sites are also shared by G1 and G2, respectively.A very comprehensive mutagenesis study (65Lappalainen P. Fedorov E.V. Fedorov A.A. Almo S.C Drubin D.G. EMBO J. 1997; 16: 5520-5530Crossref PubMed Scopus (209) Google Scholar) in which the actin interface was systematically explored concluded that cofilin did not bind in a similar manner to G1 but that there were two actin binding sites. One site comprised Arg96 and Lys98, Asp123 and Glu126, and M1 to G5, whereas the other comprised Arg80 and Lys82 and Glu134 to Arg138. These authors suggested that one of these sites bound one actin monomer within a filament, whereas the second site bound a second actin monomer. Another mutagenic study (64Jiang C.-J. Weeds A.G. Khan S. Hussey P.J. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9973-9978Crossref PubMed Scopus (45) Google Scholar) suggests the importance of the “long helix” (α3) stability in binding F-actin, but not G-actin.The actin-cofilin interface will be further understood when structural data, either from NMR or more likely, because of the molecular sizes involved, crystallography, of a complex between cofilin and actin is available. This will not be an easy task, because the interaction between the two proteins is not very strong. Ultimately, of course, we would wish to have high-resolution structures for the actin filament with and without bound cofilin. Nevertheless, our present study has provided additional firm experimental evidence for the two-sited interaction between actin and cofilin, and it will be valuable for the interpretation of any further atomic structure of their complexes. Many motile processes in cells require cyclic polymerization and depolymerization of actin filaments. In cell locomotion for example, actin is polymerized at the leading edge of the cell and is recycled by depolymerizing toward the cell center. The rate constants of pure actin have been established (1Pollard T.D. J. Cell Biol. 1986; 103: 2747-2754Crossref PubMed Scopus (584) Google Scholar), and it is clear that a discrepancy exists between these known rates and those calculated from filament turnover in cells (2Theriot J.A. Mitchison T.J. Trends Cell Biol. 1992; 2: 219-222Abstract Full Text PDF PubMed Scopus (52) Google Scholar). A host of actin-binding proteins are known that dramatically alter the behavior of actin in vitro, and of these, the cofilins have been suggested to have the correct properties to increase filament turnover in cells (3Maciver S.K. Weeds A.G. FEBS Lett. 1994; 347: 251-256Crossref PubMed Scopus (96) Google Scholar). This view has been confirmed by studies with living Saccharomyces (4Lappalainen P. Drubin D.G. Nature. 1997; 388: 78-82Crossref PubMed Scopus (363) Google Scholar) andDictyostelium (5Aizawa H. Sutoh K. Yahara I. J. Cell Biol. 1996; 132: 335-344Crossref PubMed Scopus (129) Google Scholar) and by Listeria motility assays (6Carlier M.-F. Laurent V. Santolini J. Melki R. Didry D. Xia G.-X. Hong Y. Chua N.-H. Pantaloni D. J. Cell Biol. 1997; 136: 1307-1323Crossref PubMed Scopus (820) Google Scholar, 7Rosenblatt J. Agnew B.J. Abe H. Bamburg J.R. Mitchison T.J. J. Cell Biol. 1997; 136: 1323-1332Crossref PubMed Scopus (190) Google Scholar). The cofilins are a group of low molecular mass (15–21 kDa), actin-binding proteins that depolymerize actin filaments (8Moon A. Drubin D.G. Mol. Biol. Cell. 1995; 6: 1423-1431Crossref PubMed Scopus (226) Google Scholar). This group includes vertebrate cofilin (9Nishida E. Maekawa S. Sakai H. Biochemistry. 1984; 23: 5307-5313Crossref PubMed Scopus (249) Google Scholar) and ADF1 (10Bamburg J.R. Harris H.E. Weeds A.G. FEBS Lett. 1980; 121: 178-182Crossref PubMed Scopus (158) Google Scholar), twinstar fromDrosophila (11Gunsalus K.C. Bonaccorsi S. Williams E. Verni F. Gatti M. Goldberg M.L. J. Cell Biol. 1995; 97: 1259-1263Google Scholar), depactin from echinoderms (12Mabuchi I. J. Cell Biol. 1983; 97: 1612-1621Crossref PubMed Scopus (100) Google Scholar), ADFs from plants (13Lopez I. Anthony R.G. Maciver S.K. Jiang C.-J. Khan S. Weeds A.G. Hussey P.J. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7415-7420Crossref PubMed Scopus (108) Google Scholar), Unc-60 from nematode (14McKim K.S. Matheson C. Marra M.A. Wakarchuk M.F. Baillie D.L. Mol. Gen. Genet. 1994; 242: 346-357Crossref PubMed Scopus (100) Google Scholar), cofilins fromSaccharomyces (15Moon A.L. Janmey P.A. Louie K.A. Drubin D.G. J. Cell Biol. 1993; 120: 421-435Crossref PubMed Scopus (201) Google Scholar, 16Iida K. Moriyama K. Matsumoto S. Kawasaki H. Nishida E. Yahara I. Gene. 1993; 124: 115-120Crossref PubMed Scopus (123) Google Scholar) and Dictyostelium (17Aizawa H. Sutoh K. Tsubuki S. Kawashima S. Ishii A. Yahara I. J. Biol. Chem. 1995; 270: 10923-10932Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), and actophorin from Acanthamoeba castellanii (18Cooper J.A. Blum J.D. Williamson Jr., R.C. Pollard T.D. J. Biol. Chem. 1986; 261: 477-485Abstract Full Text PDF PubMed Google Scholar). The mechanism by which cofilin depolymerizes actin filament has been contentious. Soon after the discovery of the first member of the family (10Bamburg" @default.
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• W2019933251 title "The Identification of a Second Cofilin Binding Site on Actin Suggests a Novel, Intercalated Arrangement of F-actin Binding" @default.
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