Toward understanding the kinetics of disassembly of ferritins of varying origin and subunit composition

Krausova, Katerina; Charousova, Marketa; Kratochvíl, Zdeněk; Takacsova, Paulina; Tesařová, Barbora; Sivák, Ladislav; Peskova, Marie; Sukupova, Martina; Zivotska, Hana; Makovický, Pavol; Yamashita, Ichiro; Okamoto, Naoya; Hynek, David; Haddad, Yazan; Pekařík, Vladimír; Rex, Simona; Heger, Zbyněk

doi:10.1016/j.apmt.2022.101535

Cited by 3 publications

(3 citation statements)

References 70 publications

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“…Previous research on the disassembly and assembly kinetics of ferritin has employed techniques like circular dichroism with SAXS and native PAGE, − but these methods primarily studied ferritin in bulk measurement. Disassembly kinetics at the single-molecule level have not been thoroughly investigated.…”

Section: Resultsmentioning

confidence: 99%

Structural Flexibility and Disassembly Kinetics of Single Ferritin Molecules Using Optical Nanotweezers

Yousefi,

Zheng,

Zargarbashi

et al. 2024

ACS Nano

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Ferritin, a spherical protein shell assembled from 24 subunits, functions as an efficient iron storage and release system through its channels. Understanding how various chemicals affect the structural behavior of ferritin is crucial for unravelling the origins of iron-related diseases in living organisms including humans. In particular, the influence of chemicals on ferritin's dynamics and iron release is barely explored at the single-protein level. Here, by employing optical nanotweezers using double-nanohole (DNH) structures, we examined the effect of ascorbic acid (reducing reagent) and pH on individual ferritin's conformational dynamics. The dynamics of ferritin increased as the concentration of ascorbic acid approached saturation. At pH 2.0, ferritin exhibited significant structural fluctuations and eventually underwent a stepwise disassembly into fragments. This work demonstrated the disassembly pathway and kinetics of a single ferritin molecule in solution. We identified four critical fragments during its disassembly pathway, which are 22-mer, 12-mer, tetramer, and dimer subunits. Moreover, we present single-molecule evidence of the cooperative disassembly of ferritin. Interrogating ferritin's structural change in response to different chemicals holds importance for understanding their roles in iron metabolism, hence facilitating further development of medical treatments for its associated diseases.

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Section: Resultsmentioning

confidence: 99%

Structural Flexibility and Disassembly Kinetics of Single Ferritin Molecules Using Optical Nanotweezers

Yousefi,

Zheng,

Zargarbashi

et al. 2024

ACS Nano

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show abstract

“…However, the human ferritin PNC reportedly binds high levels of albumin when exposed to serum, which may help explain its relativity-long blood circulation half-life in comparison to most other PNCs. [66] To help PNCs evade the immune system, researchers have pre-coated them with dysopsonizing albumin or even modified them to selectively bind albumin during their systemic circulation in the body. [62,67] Similarly, because TmEnc appears to adsorb albumin onto its surface over time, the action of pre-coating it with albumin before administration could also prolong its blood cir-culation.…”

Section: Protein Corona Formation and Characterizationmentioning

confidence: 99%

In Vivo Behavior of Systemically Administered Encapsulin Protein Nanocages and Implications for their use in Targeted Drug Delivery

Rennie,

Sives,

Boyton

et al. 2023

Advanced Therapeutics

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Encapsulins, self‐assembling protein nanocages derived from prokaryotes, are promising nanoparticle‐based drug delivery systems (NDDS). However, the in vivo behavior and fate of encapsulins are poorly understood. In this study, we probe the interactions between the model encapsulin from Thermotoga maritima (TmEnc) and key biological barriers encountered by NDDS. Here, a purified TmEnc formulation that exhibited colloidal stability, storability, and blood compatibility was intravenously injected into BALB/c mice. TmEnc had an excellent nanosafety profile, with no abnormal weight loss or gross pathology observed, and only temporary alterations in toxicity biomarkers detected. Notably, TmEnc demonstrated immunogenic properties, inducing the generation of nanocage‐specific IgM and IgG antibodies, but without any prolonged pro‐inflammatory effects. An absence of antibody cross‐reactivity also suggested immune‐orthogonality among encapsulins systems. Moreover, TmEnc formed a serum‐derived protein corona on its surface which changed dynamically and appeared to play a role in immune recognition. TmEnc's biodistribution profile further revealed its sequestration from the blood circulation by the liver and then biodegraded within Kupffer cells, thus indicating clearance via the mononuclear phagocyte system. Collectively, these findings provide critical insights into how encapsulins behave in vivo, thereby informing their future design, modification, and application in targeted drug delivery.This article is protected by copyright. All rights reserved

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“…However, the human ferritin PNC reportedly binds high levels of albumin when exposed to serum, which may help explain its relativity long blood circulation half-life in comparison to most other PNCs. [66] To help PNCs evade the immune system, researchers have pre-coated them with dysopsonizing albumin, or even modified them to selectively bind albumin during their systemic circulation in the body. [62,67] Similarly, because TmEnc appears to adsorb albumin onto its surface over time, the action of pre-coating it with albumin before administration could also prolong its blood circulation.…”

Section: Protein Corona Formation and Characterizationmentioning

confidence: 99%

In vivofate of systemically administered encapsulin protein nanocages and implications for their use in targeted drug delivery

Rennie,

Sives,

Boyton

et al. 2023

Preprint

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Encapsulins, self-assembling protein nanocages derived from prokaryotes, are promising nanoparticle-based drug delivery systems (NDDS). However, the in vivo behavior and fate of encapsulins are poorly understood. In this pre-clinical study, we probe the interactions between the model encapsulin from Thermotoga maritima (TmEnc) and key biological barriers encountered by NDDS. Here, a purified TmEnc formulation that exhibited colloidal stability, storability, and blood compatibility was intravenously injected into BALB/c mice. TmEnc had an excellent nanosafety profile, with no abnormal weight loss or gross pathology observed, and only temporary alterations in toxicity biomarkers detected. Notably, TmEnc demonstrated immunogenic properties, inducing the generation of nanocage-specific IgM and IgG antibodies but without any prolonged pro-inflammatory effects. An absence of antibody cross-reactivity also suggested immune-orthogonality among encapsulins systems. Moreover, TmEnc formed a serum-derived protein corona on its surface which changed dynamically and appeared to play a role in immune recognition. TmEnc's biodistribution profile further revealed its sequestration from the blood circulation by the liver and then biodegraded within Kupffer cells, thus indicating clearance via the mononuclear phagocyte system. Collectively, these findings provide critical insights into how encapsulins behave in vivo, thereby informing their future design, modification, and application in targeted drug delivery.

show abstract

Toward understanding the kinetics of disassembly of ferritins of varying origin and subunit composition

Cited by 3 publications

References 70 publications

Structural Flexibility and Disassembly Kinetics of Single Ferritin Molecules Using Optical Nanotweezers

Structural Flexibility and Disassembly Kinetics of Single Ferritin Molecules Using Optical Nanotweezers

In Vivo Behavior of Systemically Administered Encapsulin Protein Nanocages and Implications for their use in Targeted Drug Delivery

In vivofate of systemically administered encapsulin protein nanocages and implications for their use in targeted drug delivery

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