Cytochrome b561, copper, β-cleaved amyloid precursor protein and niemann-pick C1 protein are involved in ascorbate-induced release and membrane penetration of heparan sulfate from endosomal S-nitrosylated glypican-1

2017 ◽  
Vol 360 (2) ◽  
pp. 171-179 ◽  
Author(s):  
Fang Cheng ◽  
Lars-Åke Fransson ◽  
Katrin Mani
Keyword(s):  
Amyloid Precursor Protein ◽  
Heparan Sulfate ◽  
Precursor Protein ◽  
Membrane Penetration ◽  
Cytochrome B561 ◽  
Niemann Pick

scholarly journals Altered levels and distribution of amyloid precursor protein and its processing enzymes in Niemann-Pick type C1-deficient mouse brains

Glia ◽  
2010 ◽  
Vol 58 (11) ◽  
pp. 1267-1281 ◽  
Author(s):  
A. Kodam ◽  
M. Maulik ◽  
K. Peake ◽  
A. Amritraj ◽  
K. S. Vetrivel ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Deficient Mouse ◽  
Processing Enzymes ◽  
Niemann Pick

Binding of vascular heparan sulfate proteoglycan to Alzheimer's amyloid precursor protein is mediated in part by the N-terminal region of A4 peptide

1993 ◽  
Vol 627 (2) ◽  
pp. 199-204 ◽  
Author(s):  
Luc Buée ◽  
Wanhong Ding ◽  
John P. Anderson ◽  
Suree Narindrasorasak ◽  
Robert Kisilevsky ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Heparan Sulfate ◽  
Heparan Sulfate Proteoglycan ◽  
Terminal Region ◽  
Precursor Protein ◽  
Sulfate Proteoglycan

scholarly journals Interaction of the amyloid precursor protein-like protein 1 (APLP1) E2 domain with heparan sulfate involves two distinct binding modes

2015 ◽  
Vol 71 (3) ◽  
pp. 494-504 ◽  
Author(s):  
Sven O. Dahms ◽  
Magnus C. Mayer ◽  
Dirk Roeser ◽  
Gerd Multhaup ◽  
Manuel E. Than
Keyword(s):  
Amyloid Precursor Protein ◽  
Heparan Sulfate ◽  
Neuronal Development ◽  
Complex Structure ◽  
Precursor Protein ◽  
Surface Patch ◽  
Binding Modes ◽  
Heparin Binding ◽  
Positively Charged

Beyond the pathology of Alzheimer's disease, the members of the amyloid precursor protein (APP) family are essential for neuronal development and cell homeostasis in mammals. APP and its paralogues APP-like protein 1 (APLP1) and APP-like protein 2 (APLP2) contain the highly conserved heparan sulfate (HS) binding domain E2, which effects various (patho)physiological functions. Here, two crystal structures of the E2 domain of APLP1 are presented in the apo form and in complex with a heparin dodecasaccharide at 2.5 Å resolution. The apo structure of APLP1 E2 revealed an unfolded and hence flexible N-terminal helix αA. The (APLP1 E2)2–(heparin)2complex structure revealed two distinct binding modes, with APLP1 E2 explicitly recognizing the heparin terminus but also interacting with a continuous heparin chain. The latter only requires a certain register of the sugar moieties that fits to a positively charged surface patch and contributes to the general heparin-binding capability of APP-family proteins. Terminal binding of APLP1 E2 to heparin specifically involves a structure of the nonreducing end that is very similar to heparanase-processed HS chains. These data reveal a conserved mechanism for the binding of APP-family proteins to HS and imply a specific regulatory role of HS modifications in the biology of APP and APP-like proteins.

scholarly journals Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's β-secretase

2003 ◽  
Vol 163 (1) ◽  
pp. 97-107 ◽  
Author(s):  
Zoe Scholefield ◽  
Edwin A. Yates ◽  
Gareth Wayne ◽  
Augustin Amour ◽  
William McDowell ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Heparan Sulfate ◽  
Structural Characteristics ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Peptide ◽  
App Processing ◽  
Sites Of Action

Cleavage of amyloid precursor protein (APP) by the Alzheimer's β-secretase (BACE1) is a key step in generating amyloid β-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with β-site APP-cleaving enzyme (BACE) 1 and regulates its cleavage of APP. We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates. Inhibitory activity is dependent on saccharide size and specific structural characteristics, and the mechanism of action involves blocking access of substrate to the active site. In cellular assays, HS specifically inhibits BACE1 cleavage of APP but not alternative cleavage by α-secretase. Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action. Furthermore, inhibition of cellular HS synthesis results in enhanced BACE1 activity. Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing.

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