Evidence for Stepwise Formation of Amyloid Fibrils by the Mouse Prion Protein

Jain, Shweta; Udgaonkar, Jayant B.

doi:10.1016/j.jmb.2008.07.052

Cited by 83 publications

(127 citation statements)

References 74 publications

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“…PrP misfolds and oligomerizes at low pH in the presence of 150 mM NaCl (29,32). The misfolding transition has an apparent pK a of 4.7, and at pH 4, nearly all (Ͼ 95%) of the protein molecules are misfolded and oligomerized (32).…”

Section: * This Work Was Supported In Part By the Tata Institute Of Fmentioning

confidence: 99%

“…At this pH, the protein is known to be primed to misfold, which it does to near completion upon the addition of salt (28,29,32,33). Fortuitously, from the viewpoint of the applicability of the HDX methodology, pH 4 is close to the pH at which the intrinsic rate of HDX is minimal, which allows more amide hydrogens to be probed.…”

Section: * This Work Was Supported In Part By the Tata Institute Of Fmentioning

confidence: 99%

“…The full-length recombinant mouse prion protein, moPrP , encoded in the pET-17b(ϩ) plasmid was expressed in Escherichia coli BL21(DE3) CodonPlus (Stratagene) cells and purified as described previously (29). The protein was lyophilized and stored at Ϫ20°C.…”

Section: Protein Expression and Purificationmentioning

confidence: 99%

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Partially Unfolded Forms of the Prion Protein Populated under Misfolding-promoting Conditions

Moulick

Das

Udgaonkar

2015

Journal of Biological Chemistry

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Background: Folding intermediates of proteins are known to initiate misfolding. Results: Two partially unfolded forms (PUFs) of the prion protein have been characterized structurally and energetically. Conclusion: One of the PUFs is structurally similar to an initial intermediate in prion misfolding. Significance: Identification of aggregation-prone intermediates on the prion protein's folding pathway is the key to understanding its amyloidogenic propensity.

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Section: * This Work Was Supported In Part By the Tata Institute Of Fmentioning

confidence: 99%

Section: * This Work Was Supported In Part By the Tata Institute Of Fmentioning

confidence: 99%

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Partially Unfolded Forms of the Prion Protein Populated under Misfolding-promoting Conditions

Moulick

Das

Udgaonkar

2015

Journal of Biological Chemistry

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“…Initially, ␤-rich oligomers were reported to be formed at a mildly acidic pH (pH 2.5-5.0) in the presence of denaturant (7)(8)(9)(10) or at a higher temperature (11), and recently it was also reported that they were generated at a highly acidic pH (pH 2.0) without denaturant (12,13). Unfortunately, the detailed physicochemical studies at pH 2.0 were mainly on the salt-induced aggregates (13)(14)(15)(16), and the monomer state was only observed at the pH range from 5.2 to 3.0, in which a large chemical shift perturbation was observed in the C-terminal region of H2 and the H2-H3 loop (residues 185-195) (17).…”

mentioning

confidence: 99%

“…Unfortunately, the detailed physicochemical studies at pH 2.0 were mainly on the salt-induced aggregates (13)(14)(15)(16), and the monomer state was only observed at the pH range from 5.2 to 3.0, in which a large chemical shift perturbation was observed in the C-terminal region of H2 and the H2-H3 loop (residues 185-195) (17). Thus, overall conformational characteristics of PrP C at a highly acidic pH within the monomer ensemble essentially remain unknown, especially at the residue level resolution.…”

mentioning

confidence: 99%

Acid-induced Molten Globule State of a Prion Protein

Honda

Yamaguchi

Kuwata

2014

Journal of Biological Chemistry

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Background:The oligomerization mechanism of a prion protein is not fully understood. Results:We found an acid-induced molten globule state (A-state) as a pre-oligomer state, in which the Strand 1-Helix 1-Strand 2 segment was unfolded. Conclusion: The A-state formation is the initial step of the oligomerization. Significance: This work may offer a clue for understanding the prion's pathogenic conversion mechanism.

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A Transdermal Prion‐Bionics Supermolecule as a RAB3A Antagonist for Enhancing Facial Youthfulness

Liu,

Ding,

Yang

et al. 2024

Advanced Science

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The mechanism research of skin wrinkles, conducted on volunteers underwent high‐intensity desk work and mice subjected to partial sleep deprivation, revealed a significant reduction in dermal thickness associated with the presence of wrinkles. This can be attributed to the activation of facial nerves in a state of hysteria due to an abnormally elevated interaction between SNAP25 and RAB3A proteins involved in the synaptic vesicle cycle (SVC). Facilitated by AI‐assisted structural design, a refined peptide called RSIpep is developed to modulate this interaction and normalize SVC. Drawing inspiration from prions, which possess the ability to protect themselves against proteolysis and invade neighboring nerve cells through macropinocytosis, RSIpep is engineered to demonstrate a GSH‐responsive reversible self‐assembly into a prion‐like supermolecule (RSIprion). RSIprion showcases protease resistance, micropinocytosis‐dependent cellular internalization, and low adhesion with constituent molecules in the cuticle, thereby endowing it with the transdermic absorption and subsequent biofunction in redressing the frenzied SVC. As a facial mud mask, it effectively reduces periorbital and perinasal wrinkles in the human face. Collectively, RSIprion not only presents a clinical potential as an anti‐wrinkle prion‐like supermolecule, but also exemplifies a reproducible instance of bionic strategy‐guided drug development that bestows transdermal ability upon the pharmaceutical molecule.

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Evidence for Stepwise Formation of Amyloid Fibrils by the Mouse Prion Protein

Cited by 83 publications

References 74 publications

Partially Unfolded Forms of the Prion Protein Populated under Misfolding-promoting Conditions

Partially Unfolded Forms of the Prion Protein Populated under Misfolding-promoting Conditions

Acid-induced Molten Globule State of a Prion Protein

A Transdermal Prion‐Bionics Supermolecule as a RAB3A Antagonist for Enhancing Facial Youthfulness

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