Under‐folded proteins: Conformational ensembles and their roles in protein folding, function, and pathogenesis

Abstract

For decades, protein function was intimately linked to the presence of a unique, aperiodic crystal-like structure in a functional protein. The two only places for conformational ensembles of under-folded (or partially folded) protein forms in this picture were either the end points of the protein denaturation processes or transiently populated folding intermediates. Recent years witnessed dramatic change in this perception and conformational ensembles, which the under-folded proteins are, have moved from the shadow. Accumulated to date data suggest that a protein can exist in at least three global forms-functional and folded, functional and intrinsically disordered (nonfolded), and nonfunctional and misfolded/aggregated. Under-folded protein states are crucial for each of these forms, serving as important folding intermediates of ordered proteins, or as functional states of intrinsically disordered proteins (IDPs) and IDP regions (IDPRs), or as pathology triggers of misfolded proteins. Based on these observations, conformational ensembles of under-folded proteins can be classified as transient (folding and misfolding intermediates) and permanent (IDPs and stable misfolded proteins). Permanently under-folded proteins can further be split into intentionally designed (IDPs and IDPRs) and unintentionally designed (misfolded proteins). Although intrinsic flexibility, dynamics, and pliability are crucial for all under-folded proteins, the different categories of under-foldedness are differently encoded in protein amino acid sequences.

Protein structural transition at negatively charged electrode surfaces. Effects of temperature and current density

“…In both cases the profiles of BSA and HSA were almost the same (Figs 5A and 5B) while the transition curves of OVA and a-macroglobulin greatly differed from those of BSA and HSA and not so much from each other. a-macroglobulin displayed the highest stability while a-synuclein did not yield any transition in the studied I str and temperature ranges in agreement with absence of ordered structure in this natively unfolded protein [19]. Transition curves of a-macroglobulin and OVA occurred at much higher temperatures (Fig.…”

Intrinsically Disordered Proteins as Drug Targets

“…These structured elements can exist in the free protein, emerging upon conformational transitions or the combinations of both. [18][19][20] The order-disordered transitions suffered by IDPs can be produced by several factors such as exogenous perturbations (for instance pH, [21][22][23] Tª 22,[24][25][26] or macromolecular crowding) 23,[27][28][29][30] or binding (multiple) diverse molecular entities, such as proteins 18,31,32 or small molecules. 10,[33][34][35] As they are very promiscuous molecules, IDPs can bind multiple partners.…”

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“…These structured elements can exist in the free protein, emerging upon conformational transitions or the combinations of both [18][19][20]. The order-disordered transitions suffered by IDPs can be produced by several factors such as exogenous perturbations (for instance pH [21][22][23], Tª [22,[24][25][26] or macromolecular crowding [23,[27][28][29][30].…”