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Review
. 2022 Sep 14:4:285-307.
doi: 10.1016/j.crstbi.2022.09.004. eCollection 2022.

Protein conformation and biomolecular condensates

Diego S Vazquez  1 , Pamela L Toledo  1 , Alejo R Gianotti  1 , Mario R Ermácora  1
Affiliations
Review

Protein conformation and biomolecular condensates

Diego S Vazquez et al. Curr Res Struct Biol. .

Abstract

Protein conformation and cell compartmentalization are fundamental concepts and subjects of vast scientific endeavors. In the last two decades, we have witnessed exciting advances that unveiled the conjunction of these concepts. An avalanche of studies highlighted the central role of biomolecular condensates in membraneless subcellular compartmentalization that permits the spatiotemporal organization and regulation of myriads of simultaneous biochemical reactions and macromolecular interactions. These studies have also shown that biomolecular condensation, driven by multivalent intermolecular interactions, is mediated by order-disorder transitions of protein conformation and by protein domain architecture. Conceptually, protein condensation is a distinct level in protein conformational landscape in which collective folding of large collections of molecules takes place. Biomolecular condensates arise by the physical process of phase separation and comprise a variety of bodies ranging from membraneless organelles to liquid condensates to solid-like conglomerates, spanning lengths from mesoscopic clusters (nanometers) to micrometer-sized objects. In this review, we summarize and discuss recent work on the assembly, composition, conformation, material properties, thermodynamics, regulation, and functions of these bodies. We also review the conceptual framework for future studies on the conformational dynamics of condensed proteins in the regulation of cellular processes.

Keywords: Intrinsically disordered proteins; Membraneless organelles; Mesoscopic clusters; Nanocondensates; Phase separation; Protein coacervates; Protein colloids; Protein condensates; Protein conformation; Protein folding.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mario R. Ermácora reports financial support was provided by 10.13039/501100009559National University of Quilmes. 10.13039/501100002923Conicet, and 10.13039/501100003074Agencia Nacional de Promoción Científica y Tecnológica, Argentina.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Schematic protein-water phase diagram in the temperature–concentration plane. The sketch illustrates the behavior of a binary system with normal temperature dependence of the solubility, i.e., the solubility increases with temperature. Protein concentration is represented as volume fraction (Φ; see text). Below the solubility curve, supersaturated solutions are metastable and eventually undergo transitions to the condensed liquid phase or to solid-like phases, such as gel states, crystalline states, amorphous solids, and fibers. The liquid-liquid coexistence curve (short dashes), also called binodal, maps the transition to the two-phases regime, where a liquid condensed phase coexists with a liquid dilute phase. The critical temperature (TC) is the temperature above which the concentration differences between the two liquid phases vanishes and a homogeneous solution exists. At each temperature below TC, the coexistence curve defines pairs of protein concentrations, ΦL and ΦD, which characterize the protein volume fractions of the light and dense phases, respectively. The concentrations of the light and dense phases remain constant for a given temperature and are independent of the total protein concentration of the system. What changes with the total concentration of the system is the relative volume of each phase. Thus, the left arm of the coexistence curve maps the volume predominance of the light phase, whereas at the right arm predominates the volume of the dense phase. This remarkable behavior explains why at low total concentrations the system exhibits droplets of highly concentrated protein dispersed in a dilute phase, whereas at high total protein concentration droplets of dilute protein are dispersed in a dense phase. The gelation line (dots) represents the protein concentration of gel phases. The solidus line (long dashes) define the protein concentration of crystals, amorphous aggregates and fibers.
Fig. 2
Fig. 2
Simulated free energy curves and phase diagram of liquid-liquid phase separation. (A) Free energy isotherms were calculated using Eqn. 2 assuming χ(T) = a+b/T and T ​= ​300 ​K (dark blue), T ​= ​320 ​K (blue), T ​= ​340 (light blue), T ​= ​360 ​K (light red), T ​= ​370 ​K, (red). Dots mark points of equivalent chemical potential (equivalent first derivative of the free energy) and define the single common tangent of each curve. (B) The phase diagram defined by the points in panel A. The dashed line was drawn only to guide the eye, and it estimates the coexistence curve (binodal). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
The concept of overlapping volume. Two chains combining folded and disordered domains are embedded in the minimal spherical volume that include all the chain atoms. The volume intersection of the two spheres is the geometrical lens, and the larger this volume the higher the probability of intermolecular interaction and entanglement. The overlapping volume (darker gray) can be calculated from the radius of the sphere (R) and the center-to-center distance (d) using Eqn. (5).
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