STRC Research

Cofilin Severing Substoichiometric Optimum

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Cofilin Severing Substoichiometric Optimum

P2 concept. Pollard 2016 (§7) summarizes a counter-intuitive but well-established result: fully cofilin-decorated filaments are stable; severing is optimal at low cofilin occupancy because the mechanical mismatch happens at the boundary between decorated and bare segments [Pollard 2016, p.3 §7] (Andrianantoandro & Pollard 2006; Elam 2013; Ngo 2015).

The result, verbatim (paraphrased from Pollard 2016 p.3 §7)

  • Filaments saturated with cofilin are very stable.
  • Binding of small numbers of cofilins promotes severing.
  • Most likely site: interfaces between flexible decorated sites and stiffer bare segments.
  • Therefore steady-state severing is optimal at concentrations of cofilin far below the K_d.
  • High concentrations of cofilin sever transiently as the first few cofilins bind to a bare filament.

Mechanism (mechanistic chain)

  1. Cofilin binding changes the filament’s helical twist (167° → 162°) and long-pitch repeat (36 → 27 nm) — see [[Cofilin Filament Twist Geometry Change]].
  2. The decorated segment is mechanically distinct (more flexible) from the undecorated segment.
  3. At a boundary between decorated and bare, the abrupt twist mismatch causes local stress concentration.
  4. Stress concentration → severing event at the boundary.
  5. If the entire filament is decorated, no boundary exists → no preferred severing site → filament is stable.
  6. If the entire filament is bare, no decoration → no twist mismatch → no severing.

The optimum is therefore at intermediate occupancy — where the maximum density of bare/decorated boundaries exists.

Why this matters

For modeling

  • Models that use a simple severing_rate ∝ [cofilin] are wrong.
  • Correct phenomenology: severing_rate ∝ N_boundaries(occupancy), peaks near occupancy ≈ 0.5.
  • Cooperative binding of cofilin (positive cooperativity, established in Cao 2006) further focuses occupancy into clusters, raising boundary density.

For STRC h09 (hydrogel) and stereocilia

  • If a synthetic ototopical molecule perturbs cofilin activity (e.g., by competing with cofilin for an actin-binding interface), the shape of the dose-response will be non-monotonic: at low doses, you may promote severing; at high doses, you may stabilize filaments.
  • Stereocilia rootlet thinning under chronic noise exposure has been linked to cofilin/ADF activation (Drummond 2015 and follow-ups). Therapeutic strategies aiming to block rootlet damage by attenuating cofilin should target the boundary, not the occupancy — i.e., reducing cooperativity may help more than reducing total cofilin.

As a design heuristic

Whenever a regulator changes a filament’s mechanical state, look for boundary-driven behavior, not just occupancy-driven behavior. Pollard 2016 (§7) states this explicitly for cofilin; the same logic likely applies to gelsolin domain decorations and tropomyosin-isoform mosaicism.

Other regulators of cofilin (§7)

  • Aip1 cooperates with cofilin to promote severing (Chen 2015). A potential lever for biasing the severing curve.
  • Phosphorylation of Ser3 (by LIM-kinases; reversed by Slingshot/chronophin) inactivates cofilin entirely — an off-switch, not a tuning knob.
  • PIP₂ binding to cofilin also inactivates it.

Anti-fabrication notes

  • The phrase “substoichiometric optimum” is the standard summary in the field; Pollard 2016 says “optimal at concentrations of cofilin far below the K_d” (p.3 §7) but does not provide a quantitative occupancy-vs-severing curve in this review. For the curve, see Andrianantoandro & Pollard 2006 (Mol Cell) or Elam et al. 2013.
  • “Boundary mechanism” is the dominant model but not unanimous; some severing also occurs internally at decorated regions (lower rate). Don’t claim 100 % boundary attribution.

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