Metamorphic proteins and how to find them

Porter, Lauren L.; Artsimovitch, Irina; Ramírez-Sarmiento, César A.

doi:10.1016/j.sbi.2024.102807

Cited by 6 publications

(1 citation statement)

References 60 publications

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“…In fact, the existence of very different macrostates or folds, between which proteins can in fact switch physiologically, is surprisingly common [24][25][26][27]. Such proteins have been referred to as 'metamorphic' [28][29][30][31][32]. While the present versions of Alphafold cannot (and were not designed to) predict such a multiplicity of macroscopic conformations effectively [33,34] (though see their utility for isoenergetic microstates [35]), the primary sequences do in fact contain such information [36,37].…”

Section: Proteins Of Identical Sequence Can Adopt Alternative Stable ...mentioning

confidence: 99%

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Kell,

Pretorius

2024

Preprint

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In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils and fibrils exhibiting a cross-β motif of parallel or antiparallel β-sheets oriented perpendicular to the fibre direction. These protofibrils and fibrils can intertwine to form mature amyloid fibres. Similar phenomena occur in blood from individuals with circulating inflammatory molecules (also those originating from viruses and bacteria). In the presence of inflammagens, pathological clotting can occur, that results in an anomalous amyloid form termed fibrinaloid microclots. Previous proteomic analyses of these microclots have shown the presence of non-fibrin(ogen) proteins, suggesting a more complex mechanism than simple entrapment. We provide evidence against a simple entrapment model, noting that clot pores are too large and centrifugation would have removed weakly bound proteins. Instead, we explore whether co-aggregation into amyloid fibres may involve axial (multiple proteins within the same fibril), lateral (single-protein fibrils contributing to a fibre), or both types of integration. Our analysis of proteomic data from fibrinaloid microclots in different diseases shows no significant overlap with the normal plasma proteome and no correlation between plasma protein abundance and presence in microclots. Notably, abundant plasma proteins like α-2-macroglobulin, fibronectin, and transthyretin are absent from microclots, while less abundant proteins such as adiponectin, periostin, and von Willebrand Factor are well represented. Using bioinformatic tools including AmyloGram and AnuPP, we found that proteins entrapped in fibrinaloid microclots exhibit high amyloidogenic tendencies, suggesting their integration as cross-β elements into amyloid structures. This integration likely contributes to the microclots’ resistance to proteolysis. Our findings underscore the role of cross-seeding in fibrinaloid microclot formation and highlight the need for further investigation into their structural properties and implications in thrombotic and amyloid diseases. These insights provide a foundation for developing novel diagnostic and therapeutic strategies targeting amyloidogenic cross-seeding in blood clotting disorders.

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Section: Proteins Of Identical Sequence Can Adopt Alternative Stable ...mentioning

confidence: 99%

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Kell,

Pretorius

2024

Preprint

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A contact‐based analysis of local energetic frustration dynamics identifies key residues enabling RfaH fold‐switch

González‐Higueras,

Freiberger,

Galaz‐Davison

et al. 2024

Protein Science

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Fold‐switching enables metamorphic proteins to reversibly interconvert between two highly dissimilar native states to regulate their protein functions. While about 100 proteins have been identified to undergo fold‐switching, unveiling the key residues behind this mechanism for each protein remains challenging. Reasoning that fold‐switching in proteins is driven by dynamic changes in local energetic frustration, we combined fold‐switching simulations generated using simplified structure‐based models with frustration analysis to identify key residues involved in this process based on the change in the density of minimally frustrated contacts during refolding. Using this approach to analyze the fold‐switch of the bacterial transcription factor RfaH, we identified 20 residues that significantly change their frustration during its fold‐switch, some of which have been experimentally and computationally reported in previous works. Our approach, which we developed as an additional module for the FrustratometeR package, highlights the role of local frustration dynamics in protein fold‐switching and offers a robust tool to enhance our understanding of other proteins with significant conformational shifts.

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Editorial overview: Protein networks in health and disease

Komives,

Chiosis

2025

Current Opinion in Structural Biology

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Metamorphic proteins and how to find them

Cited by 6 publications

References 60 publications

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

A contact‐based analysis of local energetic frustration dynamics identifies key residues enabling RfaH fold‐switch

Editorial overview: Protein networks in health and disease

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