Elucidating the Role of Disulfide Bond on Amyloid Formation and Fibril Reversibility of Somatostatin-14

Arunagiri, Anoop; Ranganathan, Srivastav; Dhaked, Bhagwan Das; Jha, Narendra Nath; Pratihar, Supriya; Ghosh, Saikat; Sahay, Shruti; Kumar, Santosh; Das, Subhadeep; Kombrabail, Mamata; Agarwal, Kumud; Jacob, Reeba S.; Singru, Praful S.; Bhaumik, Prasenjit; Padinhateeri, Ranjith; Kumar, Ashutosh; Maji, Samir K.

doi:10.1074/jbc.m114.548354

Cited by 68 publications

(81 citation statements)

References 77 publications

(86 reference statements)

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“…After a further 30 h incubation in the presence of hemin, the short, partially formed fibrils which were present in Figure 3B disappeared completely, indicating that hemin can break down the partially formed amyloid fibrils into soluble protein, or convert them to amorphous aggregates which can be viewed in Figure 3D. Reversible fibril formation has been reported for several fibrillar proteins and peptides [39,40]. An in vivo study revealed that fibril formation of Aβ42 is initiated by nucleation, followed by reversible deposition, then by irreversible fibrillization [39].…”

Section: Hemin Dissociates Partially Formed Aβ42 Fibrilsmentioning

confidence: 65%

Hemin as a generic and potent protein misfolding inhibitor

Carver

et al. 2014

Biochemical and Biophysical Research Communications

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After the embargo period via non-commercial hosting platforms such as their institutional repository  via commercial sites with which Elsevier has an agreement In all cases accepted manuscripts should: link to the formal publication via its DOI  bear a CC-BY-NC-ND license -this is easy to do, click here to find out how  if aggregated with other manuscripts, for example in a repository or other site, be shared in alignment with our hosting policy  not be added to or enhanced in any way to appear more like, or to substitute for, the published journal article AbstractProtein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer's disease, Parkinson's disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide, and α-synuclein by blocking β-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and γs-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases. Highlights Hemin prevents Aβ42, α-synuclein, and RCM-κ-casein forming amyloid fibrils  Hemin inhibits the β-sheet structure formation of Aβ42  Hemin reduces the cell toxicity caused by fibrillar Aβ42  Hemin dissociates partially formed Aβ42 fibrils  Hemin prevents amorphous aggregation by ADH, catalase and γs-crystallin

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Section: Hemin Dissociates Partially Formed Aβ42 Fibrilsmentioning

confidence: 65%

Hemin as a generic and potent protein misfolding inhibitor

Carver

et al. 2014

Biochemical and Biophysical Research Communications

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“…These peptides were also previously shown to form nontoxic amyloids in vitro, many of which are suggested to be the storage state in secretory granules (14,50,51). Because most of these proteins/peptides were non-toxic, we chose these peptides for our cell adhesion study.…”

Section: Resultsmentioning

confidence: 99%

“…1). Sub P and somatostatin were previously reported to form unusual structures after amyloid formation (14,50,52). Amyloid formation was probed using a ThT fluorescence study.…”

Section: Resultsmentioning

confidence: 99%

Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif

Jacob¹,

George²,

Singh

et al. 2016

Journal of Biological Chemistry

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Amyloids are highly ordered, cross-␤-sheet-rich protein/peptide aggregates associated with both human diseases and native functions. Given the well established ability of amyloids in interacting with cell membranes, we hypothesize that amyloids can serve as universal cell-adhesive substrates. Here, we show that, similar to the extracellular matrix protein collagen, amyloids of various proteins/peptides support attachment and spreading of cells via robust stimulation of integrin expression and formation of integrin-based focal adhesions. Additionally, amyloid fibrils are also capable of immobilizing non-adherent red blood cells through charge-based interactions. Together, our results indicate that both active and passive mechanisms contribute to adhesion on amyloid fibrils. The present data may delineate the functional aspect of cell adhesion on amyloids by various organisms and its involvement in human diseases. Our results also raise the exciting possibility that cell adhesivity might be a generic property of amyloids.

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“…Reduction of the single disulfide bond in the functional amyloid protein somatostatin-14 in vitro results in fibrils that form faster,aremoreresistanttodenaturation,andhavedecreasedmonomer release (64). Reduction of the intrachain and/or one of two interchain disulfide bonds in porcine insulin also accelerates fibril formation (65).…”

Section: Discussionmentioning

confidence: 99%

The Kringle-like Domain Facilitates Post-endoplasmic Reticulum Changes to Premelanosome Protein (PMEL) Oligomerization and Disulfide Bond Configuration and Promotes Amyloid Formation

Watt

Spruce

et al. 2016

Journal of Biological Chemistry

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The formation of functional amyloid must be carefully regulated to prevent the accumulation of potentially toxic products. Premelanosome protein (PMEL) forms non-toxic functional amyloid fibrils that assemble into sheets upon which melanins ultimately are deposited within the melanosomes of pigment cells. PMEL is synthesized in the endoplasmic reticulum but forms amyloid only within post-Golgi melanosome precursors; thus, PMEL must traverse the secretory pathway in a non-amyloid form. Here, we identified two pre-amyloid PMEL intermediates that likely regulate the timing of fibril formation. Analyses by non-reducing SDS-PAGE, size exclusion chromatography, and sedimentation velocity revealed two native high M r disulfide-bonded species that contain Golgi-modified forms of PMEL. These species correspond to disulfide bond-containing dimeric and monomeric PMEL isoforms that contain no other proteins as judged by two-dimensional PAGE of metabolically labeled/immunoprecipitated PMEL and by mass spectrometry of affinity-purified complexes. Metabolic pulse-chase analyses, small molecule inhibitor treatments, and evaluation of site-directed mutants suggest that the PMEL dimer forms around the time of endoplasmic reticulum exit and is resolved by disulfide bond rearrangement into a monomeric form within the late Golgi or a post-Golgi compartment. Mutagenesis of individual cysteine residues within the non-amyloid cysteine-rich Kringlelike domain stabilizes the disulfide-bonded dimer and impairs fibril formation as determined by electron microscopy. Our data show that the Kringle-like domain facilitates the resolution of disulfide-bonded PMEL dimers and promotes PMEL functional amyloid formation, thereby suggesting that PMEL dimers must be resolved to monomers to generate functional amyloid fibrils.

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Elucidating the Role of Disulfide Bond on Amyloid Formation and Fibril Reversibility of Somatostatin-14

Cited by 68 publications

References 77 publications

Hemin as a generic and potent protein misfolding inhibitor

Hemin as a generic and potent protein misfolding inhibitor

Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif

The Kringle-like Domain Facilitates Post-endoplasmic Reticulum Changes to Premelanosome Protein (PMEL) Oligomerization and Disulfide Bond Configuration and Promotes Amyloid Formation

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