Keywords

IDR, Intrinsically Disordered Proteins, Structural Bias, Cellular Sensor, Polymer Physics, Phase Separation

Reference

DOI: https://doi.org/10.1016/j.tibs.2023.08.001

Abstract

Intrinsically disordered regions (IDRs) are widespread in eukaryotic proteomes and play essential biological roles without adopting stable folded structures. Instead, IDRs exist as dynamic ensembles, whose conformational biases are shaped by sequence-dependent interactions (hydrophobic, polar, electrostatic, π-π, cation-π).
Due to their solvent exposure and lack of stable tertiary structure, IDRs are inherently sensitive to environmental changes, enabling them to function as molecular sensors and actuators of cellular physicochemistry.
This review discusses the physical principles of IDR sensitivity, molecular mechanisms translating sensitivity to function, and recent examples where IDRs serve as environmental sensors.

Notes

1. General Summary

  • IDRs are not unstructured — they exhibit sequence-dependent conformational biases, influenced by a network of weak interactions (polar, electrostatic, π-π, cation-π).
  • Physicochemical environment impacts IDRs since all residues are solvent-exposed, making them highly responsive to cellular chemistry.
  • IDRs lack stable intramolecular contacts, making their conformational biases susceptible to changes in ionic strength, osmolytes, small molecules, ions, and crowding.

2. “Sequence–Ensemble–Function” Paradigm

  • IDR conformational biases enable molecular recognition:
    • Folding upon binding.
    • Tuning global dimensions for “fuzzy” complexes.
    • Modulating accessibility of motifs (e.g., transient helices).
  • IDRs influence effective concentrations of globular domains by adjusting tether length (conformational buffering).
  • Functional output is tied to sequence-encoded biases, making IDRs programmable elements in signaling.

3. IDRs as Sensors of Cellular Chemistry

  • IDRs detect environmental changes without ATP, responding rapidly (50–200 ns timescale).
  • Sensing mechanisms:
    • Global dimension changes — via balance of intramolecular attractions/repulsions.
    • Adjustments in long-range intramolecular interactions.
    • Local transient structure modulations (e.g., helices).

4. Physical Basis of Sensing: Polymer Physics View

  • Global dimension model: IDRs as homopolymers or heteropolymers with balance of attractions/repulsions quantified by self-interaction energy (ε).
  • Coil-to-globule transitions depend on chain length and interaction strength shifts.
  • IDRs as heteropolymers: chemically distinct residues create interaction matrices sensitive to solution properties.
  • Thus, IDR global dimensions and environmental responses are both sequence-dependent and tunable.


Figure: a pic from the paper for clarifying. (Click to enlarge)

5. Local Conformational Biases

  • Local structures (e.g., transient helices) are environmentally modulated, altering IDR function.
  • Example: PUMA and p53 exhibit residual helicity modulated by solution chemistry.

6. IDRs in Phase Separation and Condensates

  • IDRs contribute to biomolecular condensates, but are not always required.
  • Environmental changes influence phase behavior, affecting condensate formation.
  • Phase transitions provide “digital” (on/off) sensing, while IDR ensemble adjustments give “analog” (gradual) responses.
  • Biological systems may choose between digital and analog sensing depending on the signaling need.

7. Measuring IDR Sensitivity

In Vitro

  • Techniques: SAXS, FRET, NMR.
  • Solution space scanning:
    • Sandwich IDRs in FRET constructs.
    • Vary cosolute concentration/identity.
    • Measure ensemble dimensions (e.g., radius of gyration, end-to-end distance).
  • Use of denaturants to probe interaction strength.

In Vivo

  • Single-molecule FRET, NMR inside cells.
  • Careful distinction between direct ensemble changes vs. cellular pathway-driven responses.
  • Methods include osmotic shocks, laser-induced temperature jumps.
  • Conformational biases observed in vitro often persist in cells, although exceptions exist.

8. IDRs as Sensors in Biological Systems

  • To be true biological sensors, IDRs must respond to environmental cues and trigger functional outputs.
  • Examples of IDRs as chemical sensors:
    • CO₂ sensing: Ptc2 phosphatase.
    • pH sensing: Snf5.
    • Water deficit sensing: FLOE1 (phase separation).
    • Redox sensing: NPR1.
    • Ion/metal sensing:
      • Ca²⁺ (e.g., small-conductance potassium channels).
      • Zn²⁺, Cu²⁺, Fe³⁺, Ag⁺.
  • Suggests IDRs function as versatile sensors across a wide chemical spectrum.

RD’s Thoughts and Learnings

  • Love the idea of IDRs as “physicochemical sensors” — makes sense given their inherent plasticity and solvent exposure.
  • Polymer physics framework (self-interaction energy ε) gives a quantitative way to think about IDP responses.
  • Important distinction between analog (IDR) and digital (phase separation) sensing — RD finds this conceptualization very useful.
  • Sequence-ensemble-function model takes IDP studies to the next level — recognizing that disorder is programmable, not random.
  • Love that sensing is ATP-independent and rapid — makes IDRs uniquely suited for fast, dynamic cellular processes.
  • Clear connection to disease mechanisms — IDRs could be vulnerable to misregulation in cancer, infection, or neurodegeneration.

Take-home Messages

  • IDRs possess sequence-dependent structural biases, making them naturally suited as chemical and physical sensors in cells.
  • Environmental sensitivity of IDRs is governed by polymer physics principles and intramolecular interactions.
  • IDR conformational changes can modulate biological functions by altering binding, interactions, and phase separation.
  • IDRs are emerging as versatile, ATP-free, and rapid-response sensors in biology — a fundamental and underappreciated role.
  • RD sees this work as pivotal in redefining the functional landscape of intrinsic disorder — turning randomness into regulation.

RD loves the vision of IDRs as programmable sensors — where biology meets physics beautifully! :)