Year: 2026
Type: article
Abstract: Our understanding of protein structure rests on four pillars. Primary sequence is followed by secondary structural motifs. The third pillar is the three-dimensional organisation of single polypeptide chains. The final level includes associations between individual polypeptide chains, and incorporation of structurally essential non-peptide ligands. AlphaFold and other tools can now reliably predict tertiary structure. However, quaternary structure remains relatively poorly understood and is the least predictable element. This is at least in part because quaternary structure is the most contextually governed level. Recent data, including our own work from ribonucleotide reductase and KEAP1, show that a deeper understanding of dynamic associations and factors, such as post-translational modifications, regulating those interactions is necessary to understand and predict quaternary structure. This is particularly true in cells, where we propose that quaternary structure is better conceptualized as a state space encompassing oligomerization, binding partner availability, post-translational modifications, and localization, all governed by signaling context. We discuss how such a conceptualization helps understand and describe how quaternary structure alterations are brought about by signaling changes. Methods to decode these state-gated, structural changes, and implications for gain-of-function drug mechanism and design are also addressed. We put these considerations in context of recent protein-protein interaction prediction models, interactome profiling studies, and functional omics methods that together may be combinable to predict new protein functions linked to dynamic quaternary association changes.
Source: Frontiers in Biophysics
Authors: Daniela Diana, Yimon Aye, Marcus J. C. Long
Institutions: University of Lausanne, University of Oxford
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,353
OpenAlex ID: W7214052622