Allostery Frustrates the Experimentalist. Issue 4 (28th February 2023)

• Record Type: Journal Article
• Authors: Gianni, Stefano; Jemth, Per
• Is Part Of: Journal of molecular biology. Volume 435:Issue 4(2023)
• Publication Date: 2023-02-28
• Subjects: allostery -- allosteric networks -- protein frustration -- protein domain -- protein folding; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2022.167934
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: Allostery has been suggested as a general property of all dynamic proteins. Allosteric networks involve energetic communication between physically distant sites. Quantitative data on allosteric networks in protein domains are method dependent. Sequence conservation is influenced by structural features rather than allostery. Abstract: Proteins interact with other proteins, with nucleic acids, lipids, carbohydrates and various small molecules in the living cell. These interactions have been quantified and structurally characterized in numerous studies such that we today have a comprehensive picture of protein structure and function. However, proteins are dynamic and even folded proteins are likely more heterogeneous than they appear in most descriptions. One property of proteins that relies on dynamics and heterogeneity is allostery, the ability of a protein to change structure and function upon ligand binding to an allosteric site. Over the last decades the concept of allostery was broadened to embrace all types of long-range interactions across a protein including purely entropic changes without a conformational change in single protein domains. But with this re-definition came a problem: How do we measure allostery? In this opinion, we discuss some caveats arising from the quantitative description of single-domain allostery from an experimental perspective and how the limitations cannot be separated from the definition of allostery per se . Furthermore, we attempt to tie together allostery with the concept of frustration in an effort to investigate the links between these two complex, and yet general, properties of proteins. We arrive at the conclusion that the sensitivity to perturbation of allosteric networks in single protein domains is too large for the networks to be of significant biological relevance.