Relevance of Electrostatic Charges in Compactness, Aggregation, and Phase Separation of Intrinsically Disordered Proteins

Abstract

The abundance of intrinsic disorder in the protein realm and its role in a variety of physiological and pathological cellular events have strengthened the interest of the scientific community in understanding the structural and dynamical properties of intrinsically disordered proteins (IDPs) and regions (IDRs). Attempts at rationalizing the general principles underlying both conformational properties and transitions of IDPs/IDRs must consider the abundance of charged residues (Asp, Glu, Lys, and Arg) that typifies these proteins, rendering them assimilable to polyampholytes or polyelectrolytes. Their conformation strongly depends on both the charge density and distribution along the sequence (i.e., charge decoration) as highlighted by recent experimental and theoretical studies that have introduced novel descriptors. Published experimental data are revisited herein in the frame of this formalism, in a new and possibly unitary perspective. The physicochemical properties most directly affected by charge density and distribution are compaction and solubility, which can be described in a relatively simplified way by tools of polymer physics. Dissecting factors controlling such properties could contribute to better understanding complex biological phenomena, such as fibrillation and phase separation. Furthermore, this knowledge is expected to have enormous practical implications for the design, synthesis, and exploitation of bio-derived materials and the control of natural biological processes.

Liquid–Liquid Phase Separation by Intrinsically Disordered Protein Regions of Viruses: Roles in Viral Life Cycle and Control of Virus–Host Interactions

“…In other words, some IDPs can undergo "electrostatic collapse". Accordingly, the charge content and, most of all, the linear distribution of opposite charges, were shown to be the major determinants of protein compaction and of the amplitudes of conformational fluctuations [15,16,[26][27][28]. The scenario is, however, even more complex, as exemplified by recent studies showing that the conformational responsiveness of IDPs to charge clustering is modulated by additional sequence features, such as the proline content [29].…”

EDEM3 Domains Cooperate to Perform Its Overall Cell Functioning

“…In contrast to the PA domain that has well defined structure with large hydrophobic patches on its surface, the IDD domain is flexible and disordered. Intrinsic disordered regions adopt ensembles of configurations as in unfolded protein states [ 25 , 26 , 27 ]. This allows such regions to morph accordingly to multiple interactors and act as hubs [ 28 , 29 ].…”

Low complexity domains, condensates, and stem cell pluripotency

“…Other IDRs are characterized by clusters of positively and negative charged amino acid ( e.g. lysine, glutamic acid) interspersed with hydrophobic residues such as phenylalanine[ 25 ]. These unique amino acid compositions found in LCDs have been shown to promote LLPS by polar or charge-charge intermolecular interactions in a concentration dependent manner[ 25 , 26 ].…”