Electrostatic Collapse of Intrinsically Disordered Acid-Rich Protein Is Sensitive to Counterion Valency

TL;DR

This paper shows how the structure of a disordered protein changes in response to different types of ions, revealing a new mechanism for how these proteins compact.

Contribution

The study identifies a valency-sensitive electrostatic collapse mechanism in disordered proteins driven by specific ion binding.

Findings

Divalent cations induce collapse of AGARP at lower concentrations than monovalent cations.

Compaction occurs without forming secondary structures.

Divalent ion chelation is a key mechanism for IDP compaction in ionic environments.

Abstract

Intrinsically disordered proteins (IDPs) respond sensitively
to
their ionic environment, yet the mechanisms driving ion-induced conformational
changes remain incompletely understood. Here, we investigate how counterion
valency modulates the dimensions of an extremely charged model IDP,
the aspartic and glutamic acid-rich protein AGARP. Fluorescence correlation
spectroscopy and size exclusion chromatography reveal a pronounced,
valency-dependent reduction in its hydrodynamic radius, with divalent
cations (Ca2+, Mg2+) inducing collapse at much
lower activities than monovalent cations (Na+, K+). Molecular dynamics simulations, direct sampling, and polyampholyte
theory quantitatively capture the Debye–Hückel screening
by monovalent ions but not the enhanced compaction driven by divalent
ion binding thereby suggesting that, beyond differences in screening
strength, a valency-sensitive mode of interaction is at play. Circular
dichroism spectroscopy shows that compaction occurs without secondary
structure formation. Our results demonstrate a structure-free electrostatic
collapse and suggest that specific chelation of divalent ions by disordered
polyanionic protein chains is a key mechanism regulating IDP compaction,
with implications for understanding their behavior in biologically
relevant ionic environments.

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