Oligomerization of Human Cystatin C—An Amyloidogenic Protein: An Analysis of Small Oligomeric Subspecies

Wojciechowska, Daria; Taube, Michał; Rucińska, Karolina; Maksim, Joanna; Kozak, Maciej

doi:10.3390/ijms232113441

Cited by 4 publications

(2 citation statements)

References 42 publications

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“…Initially, the standard HCC expression and purification protocol was tested 50 . The DNA containing the HCC wild-type gene, ampicillin resistance gene, and temperature promoter was transformed and expressed in Escherichia coli BL21 (DE3) competent cells (Novagen; Sigma Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Human cystatin C induces the disaggregation process of selected amyloid beta peptides: a structural and kinetic view

Żyła,

Martel,

Jurczak

et al. 2023

Sci Rep

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Neurodegenerative diseases, such as Alzheimer’s disease (AD) and various types of amyloidosis, are incurable; therefore, understanding the mechanisms of amyloid decomposition is crucial to develop an effective drug against them for future therapies. It has been reported that one out of three people over the age of 85 are suffering from dementia as a comorbidity to AD. Amyloid beta (Aβ), the hallmark of AD, transforms structurally from monomers into β-stranded aggregates (fibrils) via multiple oligomeric states. Astrocytes in the central nervous system secrete the human cystatin C protein (HCC) in response to various proteases and cytokines. The codeposition of Aβ and HCC in the brains of patients with AD led to the hypothesis that cystatin C is implicated in the disease process. In this study, we investigate the intermolecular interactions between different atomic structures of fibrils formed by Aβ peptides and HCC to understand the pathological aggregation of these polypeptides into neurotoxic oligomers and then amyloid plaques. To characterize the interactions between Aβ and HCC, we used a complementary approach based on the combination of small-angle neutron scattering analysis, atomic force microscopy and computational modelling, allowing the exploration of the structures of multicomponent protein complexes. We report here an optimized protocol to study that interaction. The results show a dependency of the sequence length of the Aβ peptide on the ability of the associated HCC to disaggregate it.

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Section: Methodsmentioning

confidence: 99%

Human cystatin C induces the disaggregation process of selected amyloid beta peptides: a structural and kinetic view

Żyła,

Martel,

Jurczak

et al. 2023

Sci Rep

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“…However, as the environment changes from acidic to neutral, HCC tetramers break down into dimers. They concluded that the interaction of dimers generates HCC tetrameric forms without a domain-swapping mechanism, as evidenced by the breakdown of tetramers into dimers at pH 7.4 [ 18 ].…”

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confidence: 99%

Neurodegenerative Diseases: Molecular Mechanisms and Therapies

Zhou,

Kihara

2023

IJMS

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Monomer‐Dimer Equilibrium of Human Cystatin C During Internalization Into Cancer Cells

Jurczak,

Fayad,

Benard

et al. 2024

ChemBioChem

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Human cystatin C (hCC) is a physiologically important protein that serves as intra‐ and extracellular cysteine proteinase inhibitor in homeostasis. However, in pathological states it dimerizes and further oligomerizes accumulating into a toxic amyloid. HCC forms an active monomer in the extracellular space and becomes an inactive dimer when internalized in cellular organelles. However, hCC cell penetration and its oligomeric state during this process are not well understood. To determine if and how the oligomeric state influences hCC transmembrane migration, we investigated the internalization of the hCC wild type protein as well as three different mutants, which exclusively exist in the monomeric or multimeric state into HeLa cells via confocal fluorescence microscopy. Our results showed that the preferred pathway was endocytosis and that the oligomeric state did not significantly influence the internalization because both monomeric and dimeric hCC migrated into HeLa cells. Considering the differences of the active monomeric and the passive dimeric states of hCC, our findings contribute to a better understanding of the intra and extra cellular functions of hCC and their interaction with cysteine proteases.

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Oligomerization of Human Cystatin C—An Amyloidogenic Protein: An Analysis of Small Oligomeric Subspecies

Cited by 4 publications

References 42 publications

Human cystatin C induces the disaggregation process of selected amyloid beta peptides: a structural and kinetic view

Human cystatin C induces the disaggregation process of selected amyloid beta peptides: a structural and kinetic view

Neurodegenerative Diseases: Molecular Mechanisms and Therapies

Monomer‐Dimer Equilibrium of Human Cystatin C During Internalization Into Cancer Cells

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