NMR structural studies of human cystatin C dimers and monomers

Ekiel, Irena; Abrahamson, Magnus; Fulton, D. Bruce; Lindahl, P; Ac, Storer; Levadoux, Wayne; Lafrance, Martin; Labelle, S.; Pomerleau, Y.; Groleau, Denis; LeSauteur, Lynne; Gehring, Kalle

doi:10.1006/jmbi.1997.1150

Cited by 101 publications

(89 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A). Tyr-102 of cystatin C has been shown to be involved in a hydrophobic patch likely important for the integrity of the enzyme-binding surface of the inhibitor (48) A, amino acid sequence alignment of single-domain cystatins (Cys). The numbering refers to the cystatin C sequence as deduced from its cDNA, starting from the first residue of the mature protein (42,45).…”

Section: Resultsmentioning

confidence: 99%

“…2A), indicated the presence of a third disulfide bridge in addition to the two ones present in all known secretory cystatins of higher animals. Assuming a structure of cystatin F similar to those of human cystatin C and chicken cystatin (48,49), Cys-37 would be located in a loop just after an ␣-helix-forming segment, on the side of the molecule opposite from the enzyme-binding site. According to molecular modeling, this residue could be in close contact with Cys-1, provided that the extended N-terminal segment of cystatin F is stretched from the proposed anchored Gly-11 residue included in the enzyme-binding site, along the ␣-helix on the surface of the molecule.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Cystatin F Is a Glycosylated Human Low Molecular Weight Cysteine Proteinase Inhibitor

Ni¹,

Fernandez²,

Danielsson³

et al. 1998

Journal of Biological Chemistry

144

126

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Cystatin F Is a Glycosylated Human Low Molecular Weight Cysteine Proteinase Inhibitor

Ni¹,

Fernandez²,

Danielsson³

et al. 1998

Journal of Biological Chemistry

144

126

View full text Add to dashboard Cite

“…(n ¼ 8) and compared statistically using one-way ANOVA. Adhesion measurements were normalized to that of the mock clone to clearly identify the differences in tumor cell adhesion undergo N-or O-glycosylation, Ser/Thr-phosphorylation, dimerization, or to bind calcium ions (Bell et al, 1989;Laber et al, 1989;Ekiel et al, 1997;Merz et al, 1997;Taupin et al, 2000). Further studies are required to determine which of these modifications occur in cystatin M and are important for its antiproliferative function.…”

Section: Discussionmentioning

confidence: 99%

Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells

et al. 2003

View full text Add to dashboard Cite

Proteases are involved in many aspects of tumor progression, including cell survival and proliferation, escape from immune surveillance, cell adhesion and migration, remodeling and invasion of the extracellular matrix. Several lysosomal cysteine proteases have been cloned and shown to be overexpressed in cancer; yet, despite the great potential for development of novel therapeutics, we still know little about the regulation of their proteolytic activity. Cystatins such as cystatin M are potent endogenous protein inhibitors of lysosomal cysteine proteases. Cystatin M is expressed in normal and premalignant human epithelial cells, but not in many cancer cell lines. Here, we examined the effects of cystatin M expression on malignant properties of human breast carcinoma MDA-MB-435S cells. Cystatin M was found to significantly reduce in vitro: cell proliferation, migration, Matrigel invasion, and adhesion to endothelial cells. Reduction of cell proliferation and adhesion to an endothelial cell monolayer were both independent of the inhibition of lysosomal cysteine proteases. In contrast, cell migration and matrix invasion seemed to rely on lysosomal cysteine proteases, as both recombinant cystatin M and E64 were able to block these processes. This study provides the first evidence that cystatin M may play important roles in safeguarding against human breast cancer.

show abstract

“…Stefin B, a protein of 98 amino acid residues and 1 Cys, is predominantly intracellular, whereas cystatin C, a protein of 120 residues and 2 disulfide bonds, is a secretory protein. Three-dimensional structures of stefins and cystatin C have been determined, among others, the solution structure of stefin A (11) and cystatin C (12,13).…”

mentioning

confidence: 99%

Interaction between Oligomers of Stefin B and Amyloid-β in Vitro and in Cells

Škerget

Taler‐Verčič

Bavdek

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

To contribute to the question of the putative role of cystatins in Alzheimer disease and in neuroprotection in general, we studied the interaction between human stefin B (cystatin B) and amyloid-␤-(1-40) peptide (A␤). Using surface plasmon resonance and electrospray mass spectrometry we were able to show a direct interaction between the two proteins. As an interesting new fact, we show that stefin B binding to A␤ is oligomer specific. The dimers and tetramers of stefin B, which bind A␤, are domain-swapped as judged from structural studies. Consistent with the binding results, the same oligomers of stefin B inhibit A␤ fibril formation. When expressed in cultured cells, stefin B co-localizes with A␤ intracellular inclusions. It also co-immunoprecipitates with the APP fragment containing the A␤ epitope. Thus, stefin B is another APP/A␤-binding protein in vitro and likely in cells.Neurodegenerative diseases present a huge burden in the developed world's aging population. They are all in one way or another connected to aberrant protein folding and aggregation of the proteins involved (1). Various protein conformational disorders of the central and peripheral nervous system are known, which often appear sporadically but also run in families. These are among others: Parkinson and Alzheimer diseases, dementia with Lewy bodies, vascular and fronto-temporal dementia, and amyotrophic lateral sclerosis.The A␤ peptide implicated in Alzheimer disease pathology is a cleavage product of the membrane A␤ precursor protein (APP).3 It is the main constituent of extracellular amyloid plaques, however, together with its oligomers, it also resides intracellularly (2). It has been shown that A␤ oligomers prepared in vitro and those extracted from living cells exert cytotoxicity and cause symptoms of reversible memory loss in animal models (3). Amyloid protein oligomers have special structural properties, which are reflected in a common antioligomer antibody (4). This antibody not only binds the oligomers against which it was raised but also binds chaperones and some other proteins involved in disaggregating protein aggregates in cells (5). A␤-binding proteins, the so called "amateur chaperones," were suggested to have a potential in Alzheimer disease therapy (6, 7).It has been shown before that human cystatin C is an A␤-binding protein (8). Cystatins are single chain proteins that inhibit cysteine cathepsins (9). Human stefin B (also known as cystatin B) is a member of subfamily A of cystatins, classified as family I25 in the MEROPS scheme (10). Stefin B, a protein of 98 amino acid residues and 1 Cys, is predominantly intracellular, whereas cystatin C, a protein of 120 residues and 2 disulfide bonds, is a secretory protein. Three-dimensional structures of stefins and cystatin C have been determined, among others, the solution structure of stefin A (11) and cystatin C (12, 13).Human cystatin C has been found as a constituent of senile plaques of Alzheimer disease patients (14) and stefins A and B have also been reported to localize to a...

show abstract

NMR structural studies of human cystatin C dimers and monomers

Cited by 101 publications

References 44 publications

Cystatin F Is a Glycosylated Human Low Molecular Weight Cysteine Proteinase Inhibitor

Cystatin F Is a Glycosylated Human Low Molecular Weight Cysteine Proteinase Inhibitor

Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells

Interaction between Oligomers of Stefin B and Amyloid-β in Vitro and in Cells

Contact Info

Product

Resources

About