Characteristics of C-terminal, β-amyloid peptide binding fragment of neuroprotective protease inhibitor, cystatin C
PBN-AR
Instytucja
Wydział Chemii (Uniwersytet Gdański)
Źródłowe zdarzenia ewaluacyjne
Informacje podstawowe
Główny język publikacji
en
Czasopismo
Journal of Molecular Recognition (25pkt w roku publikacji)
ISSN
0952-3499
EISSN
1099-1352
Wydawca
DOI
URL
Rok publikacji
2017
Numer zeszytu
2
Strony od-do
1-13
Numer tomu
30
Identyfikator DOI
Liczba arkuszy
0.6
Słowa kluczowe
en
Alzheimer' s disease
amyloid
cerebral amyloidosis
cystatin C
neurodegeneration
Streszczenia
Język
en
Treść
Cystatin C originally identified as a cysteine proteases inhibitor has a broad spectrum of biolog- ical roles ranging from inhibition of extracellular cysteine protease activities, bone resorption, and modulation of inflammatory responses to stimulation of fibroblasts proliferation. There is an increasing number of evidence to suggest that human cystatin C (hCC) might play a protective role in the pathophysiology of sporadic Alzheimer ’ s disease. In vivo and in vitro results well documented the association of hCC with A β and the hCC ‐ induced inhibition of A β fibril formation. In our earlier work, using a combination of selective proteolytic methods and MS spectroscopy, C ‐ terminal fragment hCC(101 ‐ 117) was identified as the A β ‐ binding region. The fragment of A β peptide responsible for the complex formation with hCC was found in the middle, highly hydrophobic part, A β (17 ‐ 24). Structures and affinities of both A β and hCC binding sites were characterized by the enzyme ‐ linked immunosorbent assay ‐ like assay, by surface plasmon resonance, and by nano ‐ ESI ‐ FTICR MS of the hCC – A β ‐ binding peptide complexes. In the in vitro inhibition studies, the binding cystatin sequence, hCC(101 ‐ 117), revealed the highest relative inhibitory effect toward A β ‐ fibril formation. Herein, we present further studies on molecular details of the hCC ‐ A β complex. With Ala substi- tution, affinity experiments, and enzyme ‐ linked immunosorbent assay ‐ like assays for the A β ‐ binding fragment, hCC(101 ‐ 117), and its variants, the importance of individual amino acid resi- dues for the protein interaction was evaluated. The results were analyzed using hCC(101 ‐ 117) nuclear magnetic resonance structural data with molecular dynamics calculations and molecular modeling of the complexes. The results point to conformational requirements and special impor- tance of some amino acid residues for the protein interaction. The obtained results might be helpful for the design of low molecular compounds modulating the biological role of both proteins. Copyright © 2016 John Wiley & Sons, Ltd
Inne
System-identifier
UOG966c5338607a4cabae0b94aa67c4c1c6
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