Cofilin

Cartoon representation of a cofilin (actin depolymerizing factor, ADF).

ADF/cofilin is a family of actin-binding proteins which disassembles actin filaments. Three highly conserved and highly (70%-82%) identical genes belonging to this family have been described in humans and mice:

Actin-binding proteins regulate assembly and disassembly of actin filaments.[1] Cofilin, a member of the ADF/cofilin family is actually a protein with 70% sequence identity to ADF, making it part of the ADF/cofilin family of small ADP-binding proteins.[2][3] The protein binds to actin monomers and filaments, G actin and F actin, respectively.[4] Cofilin causes depolymerization at the minus end of filaments, thereby preventing their reassembly. The protein is known to sever actin filaments by creating more positive ends on filament fragments.[1] Cofilin/ADF(destrin) is likely to sever F-actin without capping [3] and prefers ADP-actin. These monomers can be recycled by profilin, activating monomers to go back into filament form again by an ADP-to-ATP exchange. ATP-actin is then available for assembly.[1]

Structure

Cofilin binds monomeric (G-actin) and filamentous actin (F-actin). Its binding affinities are higher for ADP-actin over ADP-Pi and ATP-actin. Its binding changes the twist of F-actin. The structure of ADF was first characterized in 1980 by James Bamburg.[5] Four actin histidines near the cofilin binding site may be needed for cofilin/actin interaction, but pH sensitivity alone may not be enough of an explanation for the levels of interaction encountered. Cofilin is accommodated in ADP-F actin because of increased flexibility in this form of actin. Binding by both cofilin and ADF(destrin) causes the crossover length of the filament to be reduced. Therefore, strains increase filament dynamics and the level of filament fragmentation observed.[3]

Function

Cofilin is a ubiquitous actin-binding factor required for the reorganization of actin filaments. ADF/Cofilin family members bind G-actin monomers and depolymerize actin filaments through two mechanisms: severing[6] and increasing the off-rate for actin monomers from the pointed end.[7] "Older" ADP/ADP-Pi actin filaments free of tropomyosin and proper pH are required for cofilin to function effectively. In the presence of readily available ATP-G-actin cofilin speeds up actin polymerization via its actin-severing activity (providing free barbed ends for further polymerization and nucleation by the Arp2/3 complex).[8] As a long-lasting in vivo effect, cofilin recycles older ADP-F-actin, helping cell to maintain ATP-G-actin pool for sustained motility. pH, phosphorylation and phosphoinositides regulate cofilin’s binding and associating activity with actin[4]

The Arp2/3 complex and cofilin work together to reorganize the actin filaments in the cytoskeleton. Arp 2/3, an actin binding proteins complex, binds to the side of ATP-F-actin near the growing barbed end of the filament, causing nucleation of a new F-actin branch,[8] while cofilin-driven depolymerization takes place after dissociating from the Arp2/3 complex.[1] They also work together to reorganize microtubules in order to traffic more proteins by vesicle to continue the growth of filaments.[9]

Cofilin also binds with other proteins such as myosin, tropomyosin, α-actinin, gelsolin and scruin. These proteins compete with cofilin for actin binding.[3] Сofilin also play role in innate immune response.

In a Model Organism

ADF/cofilin is found in ruffling membranes and at the leading edge of mobile cells.[7] In particular, ADF/cofilin promotes disassembly of the filament at the rear of the brush in Xenopus laevis lamellipodia, a protrusion from fibroblast cells characterized by actin networks. Subunits are added to barbed ends and lost from rear-facing pointed ends. Increasing the rate constant, k, for actin dissociation from the pointed ends was found to sever actin filaments. Through this experimentation, it was found that ATP or ADP-Pi are probably involved in binding to actin filaments.[9]

References

  1. 1 2 3 4 Cooper, G. M. and R. E. Hausman. The Cell: A Molecular Approach, 3rd ed. Washington DC: ASM Press 2004 pp.436-440.
  2. ↑ Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC (2015). "The evolution of compositionally and functionally distinct actin filaments". Journal of Cell Science. 128 (11): 2009–19. PMID 25788699. doi:10.1242/jcs.165563.
  3. 1 2 3 4 McGough A, Pope B, Chiu W, Weeds A (August 1997). "Cofilin changes the twist of F-actin: implications for actin filament dynamics and cellular function". J. Cell Biol. 138 (4): 771–81. PMC 2138052 Freely accessible. PMID 9265645. doi:10.1083/jcb.138.4.771.
  4. 1 2 Lappalainen P, Drubin DG (July 1997). "Cofilin promotes rapid actin filament turnover in vivo". Nature. 388 (6637): 78–82. PMID 9214506. doi:10.1038/40418.
  5. ↑ Bamburg, JR; Harris, HE; Weeds, AG (17 November 1980). "Partial purification and characterization of an actin depolymerizing factor from brain.". FEBS Lett. 121 (1): 178–82. PMID 6893966. doi:10.1016/0014-5793(80)81292-0.
  6. ↑ Ichetovkin I, Han J, Pang KM, Knecht DA, Condeelis JS (April 2000). "Actin filaments are severed by both native and recombinant dictyostelium cofilin but to different extents". Cell Motil. Cytoskeleton. 45 (4): 293–306. PMID 10744862. doi:10.1002/(SICI)1097-0169(200004)45:4<293::AID-CM5>3.0.CO;2-1.
  7. 1 2 Carlier MF, Laurent V, Santolini J, et al. (March 1997). "Actin depolymerizing factor (ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility". J. Cell Biol. 136 (6): 1307–22. PMC 2132522 Freely accessible. PMID 9087445. doi:10.1083/jcb.136.6.1307.
  8. 1 2 Ichetovkin I, Grant W, Condeelis J (January 2002). "Cofilin produces newly polymerized actin filaments that are preferred for dendritic nucleation by the Arp2/3 complex". Curr. Biol. 12 (1): 79–84. PMID 11790308. doi:10.1016/s0960-9822(01)00629-7.
  9. 1 2 Svitkina TM, Borisy GG (May 1999). "Arp2/3 complex and actin depolymerizing factor/cofilin in dendritic organization and treadmilling of actin filament array in lamellipodia". J. Cell Biol. 145 (5): 1009–26. PMC 2133125 Freely accessible. PMID 10352018. doi:10.1083/jcb.145.5.1009.

See also

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