Factors influencing actin filament length and treadmilling


Essential Info: Actin Filaments and Mechanotransduction

4.3.1. Factors influencing actin filament length and treadmilling

1. ATP binding on G-actin and free ATP-G-actin concentration

ATP-binding on actin subunits modulates the dynamics of filament assembly, with ATP-binding generally favoring intersubunit interactions and thereby filament assembly [1]. The rate of actin addition to filaments depends on the concentration of free ATP-G-actin whereas the rate of subunit loss does not. At high free ATP-G-actin concentrations the rate of addition exceeds the rate of dissociation which results in actin filament growth.

2. The rate of ATP-G-actin assembly to the ends

The addition of ATP-G-actin to the two ends of preexisting actin filaments occurs at very different rates (see Table 1) [2]. The addition of free ATP-G-actin at the (-) end is much lower relative to the (+) end, however, the rates of dissociation between the two ends is approximately the same.

3. The critical concentration can be adjusted

The (-) and (+) ends have a different criticial concentration (Cc) for actin filament growth. The Cc is defined as the concentration level of free ATP-G-actin where the rate of addition is balanced by the rate of loss and no net growth occurs at that end. At concentrations above the Cc, actin filament growth occurs, wheras below it, there is a loss of subunits and shrinkage occurs. Any protein that alters the Cc, e.g. profilin, will alter actin filament dynamics.

4. Actin binding drugs

Toxins such as phalloidins, cytochalasins, latrunculin A, and jasplakinolide are naturally occurring small molecules that bind to actin and alter its polymerization. Phalloidins inhibit actin filament disassembly by locking adjacent actin subunits together, while cytochalasins bind to the barbed end of actin filaments to prevent actin filament assembly and disassembly at that end (reviewed in [3]). Latrunculin A binds to actin monomers to inhibit their polymerization and thus promotes filament disassembly; latrunculin A may also inhibit nucleotide exchange on actin subunits [4, 5]. Jasplakinolides stabilize actin monomers, thereby enhancing filament nucleation and assembly.

5. Actin binding proteins (see Figures below):

Certain actin binding proteins initiate actin filament assembly/disassembly directly, while others influence the factors listed in items 1-3 above. There are over 60 families of actin-binding proteins (reviewed in [6]) with the main actin monomer-binding proteins in vertebrate cells being thymosin-β4 and profilin. Thymosin-β4 binds strongly to ATP-actin and prevents its assembly into filaments [7]. Because profilin and thymosin-β4 have overlapping binding sites on actin [8, 9], profilin must compete with thymosin-β4 during filament assembly [10]. Other examples of actin-binding proteins include: Arp2/3 complex, formin, fascin, WASp, and capping protein.


Figure: Accessory proteins control actin filament length. Actin filament growth is controlled by the rate of G-actin assembly and disassembly from the barbed and pointed ends, respectively. The filament length remains constant when the rate of assembly and disassembly are equal. This figure is adapted from [11].

Figure: Actin binding proteins influence actin dynamics. A. Treadmilling of actin filaments can be altered by profilin and ADF which generally increase and decrease the size of actin filaments, respectively. B. New filaments are nucleated by the ARP2/3 complex, which binds both G-actin monomers and the side of actin filaments to nucleate new filaments or branches. Formins nucleate new filaments by binding G-actin and through cooperation with profilin. C. Actin cross-linking proteins influence the packing and organization of actin filaments into secondary structures. D. Capping and severing proteins promote disassembly of actin filaments. E. Actin filament assembly can be modulated by events such as controlled nucleotide hydrolysis (e.g. ATP on actin) and reversible modifications (e.g. phosphorylation) on components that control actin assembly.

References

  1. Carlier MF. & Pantaloni D. Control of actin dynamics in cell motility. J. Mol. Biol. 1997; 269(4):459-67. [PMID: 9217250]
  2. Pollard TD. Rate constants for the reactions of ATP- and ADP-actin with the ends of actin filaments. J. Cell Biol. 1986; 103(6 Pt 2):2747-54. [PMID: 3793756]
  3. Cooper JA. Effects of cytochalasin and phalloidin on actin. J. Cell Biol. 1987; 105(4):1473-8. [PMID: 3312229]
  4. Yarmola EG., Somasundaram T., Boring TA., Spector I. & Bubb MR. Actin-latrunculin A structure and function. Differential modulation of actin-binding protein function by latrunculin A. J. Biol. Chem. 2000; 275(36):28120-7. [PMID: 10859320]
  5. Morton WM, Ayscough KR, McLaughlin PJ. Latrunculin alters the actin-monomer subunit interface to prevent polymerization. Nat Cell Biol, 2000 Jun;2(6):376-8. [PMID: 10854330]
  6. Pollard TD. Introduction to actin and actin-binding proteins. In Guidebook to the Cytoskeletal and Motor Proteins, ed. Kreis RV, pp3-11. Oxford, UK: Oxford univ. Press. 2nd ed. ISBN: 0198599358
  7. Carlier MF., Jean C., Rieger KJ., Lenfant M. & Pantaloni D. Modulation of the interaction between G-actin and thymosin beta 4 by the ATP/ADP ratio: possible implication in the regulation of actin dynamics. Proc. Natl. Acad. Sci. U.S.A. 1993; 90(11):5034-8. [PMID: 8506348]
  8. Safer D., Sosnick TR. & Elzinga M. Thymosin beta 4 binds actin in an extended conformation and contacts both the barbed and pointed ends. Biochemistry 1997; 36(19):5806-16. [PMID: 9153421]
  9. Schutt CE., Myslik JC., Rozycki MD., Goonesekere NC. & Lindberg U. The structure of crystalline profilin-beta-actin. Nature 1993; 365(6449):810-6. [PMID: 8413665]
  10. Kang F, Purich DL, & Southwick FS. Profilin promotes barbed-end actin filament assembly without lowering the critical concentration. J Biol Chem 1999, 274(52):36963-36972. [PMID: 10601251]
  11. Athman R., Louvard D. & Robine S. The epithelial cell cytoskeleton and intracellular trafficking. III. How is villin involved in the actin cytoskeleton dynamics in intestinal cells? Am. J. Physiol. Gastrointest. Liver Physiol. 2002; 283(3):G496-502. [PMID: 12181160]
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Sruthi Jagannathan,
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