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The 68K protease has beta-secretase-like activity for lymphocyte precursor protein but not for brain substrate.

https://arctichealth.org/en/permalink/ahliterature199515
Source
Neuroreport. 2000 Feb 7;11(2):373-7
Publication Type
Article
Date
Feb-7-2000
Author
A. Matsumoto
Author Affiliation
Department of Radiation Biophysics and Genetics, Kobe University School of Medicine, Japan.
Source
Neuroreport. 2000 Feb 7;11(2):373-7
Date
Feb-7-2000
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Alzheimer Disease - enzymology
Amino Acid Sequence
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor - metabolism
Aspartic Acid Endopeptidases - metabolism
Blotting, Western
Cells, Cultured
Cerebral Cortex - enzymology
Chondroitin ABC Lyase - metabolism
Endopeptidases
Female
Humans
Isoenzymes - metabolism
Lymphocytes - cytology - enzymology
Male
Middle Aged
Molecular Sequence Data
Organ Specificity
Peptide Fragments - chemistry
Polysaccharide-Lyases - metabolism
Protein Processing, Post-Translational
Sequence Analysis, Protein
Serine Endopeptidases - metabolism
Substrate Specificity
Abstract
Processing and metabolism of beta-amyloid precursor protein (APP) and generation of a variety of beta-amyloid (Abeta) peptides in the human brain is essentially associated with pathophysiology of Alzheimer's disease (AD). APP degradation activity of the 68 kDa serine protease, which was originally prepared from familial AD lymphoblastoid cells and harbors beta-secretase-like activity, was analyzed by Western blot using anti Abeta 1/40 antibody and anti APP cytoplasmic domain (CT) antibody. Native lymphocyte APP (LAPP) prepared from normal or AD-derived lymphoblastoid cells was degraded by the protease, generating a 16 kDa Abeta-bearing C-terminal fragment of APP. N-terminal amino acid sequencing of the fragment indicated that the protease cleaves LAPP at the Abeta-N-terminus. When the LAPP was treated with chondroitinase ABC prior to proteolysis, the activity to generate the fragment was inhibited, but pretreatment with heparitinase resulted in no effect. Native hippocampal APP prepared from normal brain, however, did not generate the 16 kDa peptide by the protease treatment. These results suggest that the process of APP degradation and Abeta-peptides generation, including beta-secretase activity, is associated with tissue specificity of both APP substrate and proteases. They also indicate that sulfated glycoconjugates attached to a portion of APP isoforms may play a role as a molecular determinant in the proteolysis.
PubMed ID
10674489 View in PubMed
Less detail

Aggregation and catabolism of disease-associated intra-Abeta mutations: reduced proteolysis of AbetaA21G by neprilysin.

https://arctichealth.org/en/permalink/ahliterature156321
Source
Neurobiol Dis. 2008 Sep;31(3):442-50
Publication Type
Article
Date
Sep-2008
Author
Vicki Betts
Malcolm A Leissring
Georgia Dolios
Rong Wang
Dennis J Selkoe
Dominic M Walsh
Author Affiliation
Laboratory for Neurodegenerative Research, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Republic of Ireland.
Source
Neurobiol Dis. 2008 Sep;31(3):442-50
Date
Sep-2008
Language
English
Publication Type
Article
Keywords
Alzheimer Disease - genetics - metabolism - physiopathology
Amino Acid Sequence - genetics
Amino Acid Substitution - genetics
Amyloid beta-Peptides - chemistry - genetics - metabolism
Amyloid beta-Protein Precursor - chemistry - genetics - metabolism
Brain Chemistry - genetics
Fibrinolysin - chemistry - metabolism
Humans
Insulysin - chemistry - metabolism
Mass Spectrometry
Mutation - genetics
Neprilysin - chemistry - metabolism
Peptide Fragments - chemistry - genetics - metabolism
Peptide Hydrolases - metabolism
Plaque, Amyloid - chemistry - metabolism
Protein Structure, Tertiary - genetics
Abstract
Five point mutations within the amyloid beta-protein (Abeta) sequence of the APP gene are associated with hereditary diseases which are similar or identical to Alzheimer's disease and encode: the A21G (Flemish), E22G (Arctic), E22K (Italian), E22Q (Dutch) and the D23N (Iowa) amino acid substitutions. Although a substantial body of data exists on the effects of these mutations on Abeta production, whether or not intra-Abeta mutations alter degradation and how this relates to their aggregation state remain unclear. Here we report that the E22G, E22Q and the D23N substitutions significantly increase fibril nucleation and extension, whereas the E22K substitution exhibits only an increased rate of extension and the A21G substitution actually causes a decrease in the extension rate. These substantial differences in aggregation together with our observation that aggregated wild type Abeta(1-40) was much less well degraded than monomeric wild type Abeta(1-40), prompted us to assess whether or not disease-associated intra-Abeta mutations alter proteolysis independent of their effects on aggregation. Neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin play a major role in Abeta catabolism, therefore we compared the ability of these enzymes to degrade wild type and mutant monomeric Abeta peptides. Experiments investigating proteolysis revealed that all monomeric peptides are degraded similarly by IDE and plasmin, but that the Flemish peptide was degraded significantly more slowly by NEP than wild type Abeta or any of the other mutant peptides. This finding suggests that resistance to NEP-mediated proteolysis may underlie the pathogenicity associated with the A21G mutation.
Notes
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PubMed ID
18602473 View in PubMed
Less detail

[An analysis of the cDNA nucleotide sequence for the C-terminal fragment of the coat protein in tobacco mosaic virus isolates from tobacco growing in an ecological niche of Polesye, Ukraine]

https://arctichealth.org/en/permalink/ahliterature69071
Source
Tsitol Genet. 1998 Apr-May;32(3):30-5
Publication Type
Article
Author
A L Boiko
S A Stepaniuk
O M Garifulin
Source
Tsitol Genet. 1998 Apr-May;32(3):30-5
Language
Russian
Publication Type
Article
Keywords
Amino Acid Sequence
Base Sequence
Capsid - chemistry - genetics
Cesium radioisotopes
Cloning, Molecular - methods
DNA, Complementary - genetics
DNA, Viral - genetics
Ecosystem
English Abstract
Molecular Sequence Data
Peptide Fragments - chemistry - genetics
Plants, Toxic
Radioactive Pollutants
Tobacco - virology
Tobacco Mosaic Virus - genetics - isolation & purification
Ukraine
Abstract
Two identical strains of tobacco type TVM have been isolated in the region with 137Cs nuclear contamination with density of 12.6 Cu/km2 recombinant plasmids (pTVM9, pTVM9,5) containing cDNA of complete provirus and C-end sequence of cDNA of specific capsid protein from one of isolated viruses have been obtained. The capsule proteins of isolated strains have the higher 19.5 +/- 1.9 kDa molecular weight than standard TVM strain (17.5 kDa) as to SDS-PAAG electrophoresis data. No differences in distribution of fragments immunoactive to control antiserum have been found when using immunoblot analysis of capsid proteins of isolates and standard strain treated by tripsin. Sequencing analysis of cDNA pTVM9,5 has revealed non-conservative amino acid replacement of serine by tyrosine in position 149 for homologous region of capsid protein of standard TVM strain, which allows to suppose the mediated effect of specific ecological situation on the appearance of such replacement.
PubMed ID
9879105 View in PubMed
Less detail

Androgen-sensitive human prostate cancer cells, LNCaP, produce both N-terminally mature and truncated prostate-specific antigen isoforms.

https://arctichealth.org/en/permalink/ahliterature21491
Source
Eur J Biochem. 1998 Jul 15;255(2):329-35
Publication Type
Article
Date
Jul-15-1998
Author
A. Herrala
R. Kurkela
M. Vihinen
N. Kalkkinen
P. Vihko
Author Affiliation
Biocenter Oulu and WHO Collaborating Centre for Research on Reproductive Health, University of Oulu, Finland.
Source
Eur J Biochem. 1998 Jul 15;255(2):329-35
Date
Jul-15-1998
Language
English
Publication Type
Article
Keywords
Amino Acid Sequence
Computer Graphics
Gene Expression Regulation, Neoplastic - drug effects
Humans
Male
Metribolone - pharmacology
Models, Molecular
Molecular Weight
Peptide Fragments - chemistry
Prostate-Specific Antigen - biosynthesis - chemistry - isolation & purification
Prostatic Neoplasms - metabolism
Protein Conformation
Recombinant Proteins - biosynthesis - chemistry - isolation & purification
Research Support, Non-U.S. Gov't
Semen - chemistry
Testosterone Congeners - pharmacology
Tumor Cells, Cultured
Abstract
To characterize prostate-specific antigen (PSA) produced by cancer cells, different isoforms of PSA secreted by the human prostate cancer cells, LNCaP, were purified. LNCaP-PSA production was induced by synthetic androgen, R1881. LNCaP-PSA was separated into four pools. The molecular mass of LNCaP-PSA isoforms in these pools was 34 kDa under reducing conditions and 29 kDa under nonreducing conditions on SDS/PAGE. pI of LNCaP-PSA isoforms varied from 6.8 to 8.2. Pool A had the highest specific activity, 37 nmol/(min x mg). All the pools formed stable complexes with alpha1-antichymotrypsin and alpha2-macroglobulin. The pools contained 10-60% of N-terminally correctly processed LNCaP-PSA isoforms. According to the molecular modelling, the addition or deletion of two or four N-terminal amino acids could affect the three-dimensional structure and thereby remarkably reduce the enzyme activity of LNCaP-PSA.
PubMed ID
9716373 View in PubMed
Less detail

The Arctic mutation alters helix length and type in the 11-28 beta-amyloid peptide monomer-CD, NMR and MD studies in an SDS micelle.

https://arctichealth.org/en/permalink/ahliterature100702
Source
J Struct Biol. 2008 Nov;164(2):199-209
Publication Type
Article
Date
Nov-2008
Author
Sylwia Rodziewicz-Motowidlo
Paulina Czaplewska
Emilia Sikorska
Marta Spodzieja
Aleksandra S Kolodziejczyk
Author Affiliation
Faculty of Chemistry, University of Gdansk, Sobieskiego 18, 80-952 Gdansk, Pomorskie, Poland. sylwia@chem.univ.gda.pl
Source
J Struct Biol. 2008 Nov;164(2):199-209
Date
Nov-2008
Language
English
Publication Type
Article
Keywords
Amyloid beta-Peptides - chemistry - genetics
Circular Dichroism
Humans
Magnetic Resonance Spectroscopy
Micelles
Molecular Dynamics Simulation
Mutation, Missense
Peptide Fragments - chemistry - genetics
Protein Structure, Secondary - genetics
Sodium Dodecyl Sulfate
Abstract
The beta-amyloid (Abeta) is the major peptide constituent of neuritic plaques in Alzheimer's disease, and its aggregation is believed to play a central role in the pathogenesis of the disease. Naturally occurring mutations resulting in changes in the Abeta sequence (pos. 21-23) are associated with familial Alzheimer's-like diseases with extensive cerebrovascular pathology. It has been demonstrated that such mutations alter the aggregation ability of Abeta and its neurotoxicity. Among the five mutations at positions 21-23 there is one with distinct clinical characteristics and a potentially distinct pathogenic mechanism-the Arctic (E22G) mutation. We have examined the structures of fragment 11-28 of the native peptide and its E22G variant. This fragment was chosen because it has been shown to be a good model for conformational and aggregation studies as it contains the hydrophobic core responsible for aggregation and the residues critical to alpha-secretase cleavage of APP. The detailed structure of the two peptides was determined using CD, 2D NMR and molecular dynamics techniques under water-SDS micelle conditions. Our studies indicated the existence of partially alpha- and 3(10)-helical conformations in the native and mutated peptide, respectively.
PubMed ID
18765285 View in PubMed
Less detail

B-cell epitopes in HIV-1 Tat and Rev proteins colocalize with T-cell epitopes and with functional domains.

https://arctichealth.org/en/permalink/ahliterature209696
Source
Biomed Pharmacother. 1997;51(10):480-7
Publication Type
Article
Date
1997
Author
M. Tähtinen
A. Ranki
S L Valle
V. Ovod
K. Krohn
Author Affiliation
University of Tampere, Finland.
Source
Biomed Pharmacother. 1997;51(10):480-7
Date
1997
Language
English
Publication Type
Article
Keywords
Amino Acid Sequence
B-Lymphocytes - immunology - virology
Epitopes - analysis
Finland
Gene Products, rev - biosynthesis - chemistry - genetics
Gene Products, tat - biosynthesis - chemistry - genetics
HIV Infections - immunology
HIV Seronegativity - immunology
HIV Seropositivity - immunology
HIV-1 - genetics - immunology
Humans
Molecular Sequence Data
Peptide Fragments - chemistry
T-Lymphocytes - immunology - virology
rev Gene Products, Human Immunodeficiency Virus
tat Gene Products, Human Immunodeficiency Virus
Abstract
We describe the characterization of the B-cell epitopes of HIV-1 regulatory proteins Tat and Rev. The prevalence of antibodies to these proteins among human immunodeficiency virus (HIV)-1-infected individuals was examined by enzyme-linked immunosorbent assay (ELISA) and by Western blotting. The Tat and Rev antibody-positive sera were selected for epitope mapping performed with partially overlapping synthetic peptides bound to polyethylene pins. Eighteen and twelve percent of HIV-infected individuals had antibodies against Tat or Rev, respectively. In Tat, four epitopic regions were identified, situated within amino acids 6-10 (PRLEP), 21-37 (ACTNCYCKKCCFHCQVC), 39-58 (ITKALGISYGRKKRRQRRRA) and 74-82 (TSQSRGDPT). The most frequently recognized epitopic regions were located in the middle of the protein. In Rev, the two most frequently recognized epitopic regions were near the amino terminus of the protein within amino acids 12-20 (LIRTVRLIK) and 38-49 (RRNRRRRWRERQ). A third epitope was mapped around amino acids 55-62 (ISERILGT) and a fourth around amino acids 78-83 (LERLTU). To analyze the specificity of Tat and Rev epitopes, soluble synthetic peptides representing the identified epitopes were used in an ELISA assay, and the recognition of most epitopes was shown to be specific for HIV-1-infected individuals. In addition, many of the Tat and Rev epitopes were shown to overlap with regions having functional activity or with regions previously identified as T-cell epitopes.
PubMed ID
9863510 View in PubMed
Less detail

Effect of enzymatic modification of dietary wheat flour for reducing its allergenicity on oral sensitization to and intestinal absorption of ovalbumin.

https://arctichealth.org/en/permalink/ahliterature57414
Source
Biosci Biotechnol Biochem. 2003 Nov;67(11):2483-5
Publication Type
Article
Date
Nov-2003
Author
Ryo Saito
Natsu Yamaguchi
Kei Sonoyama
Jun Kawabata
Author Affiliation
Laboratory of Food Biochemistry, Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Saporo, Japan.
Source
Biosci Biotechnol Biochem. 2003 Nov;67(11):2483-5
Date
Nov-2003
Language
English
Publication Type
Article
Keywords
Allergens - chemistry - immunology
Amino Acid Sequence
Animals
Flour
Humans
Immunization
Immunoglobulin G - blood
Intestinal Absorption - physiology
Mice
Mice, Inbred BALB C
Ovalbumin - blood - pharmacokinetics
Peptide Fragments - chemistry
Rats
Rats, Inbred BN
Research Support, Non-U.S. Gov't
Triticum - immunology
Abstract
Increase in plasma immunoglobulin G specific to orally administered ovalbumin in Brown Norway rats was retarded by feeding enzyme-treated wheat flour when compared with untreated flour. Because plasma ovalbumin concentrations after feeding ovalbumin tended to be lower in mice fed enzyme-treated flour than in those fed untreated flour, suppression of ovalbumin absorption may be relevant to retarded sensitization observed in rats.
PubMed ID
14646216 View in PubMed
Less detail

Effects of the amyloid precursor protein Glu693-->Gln 'Dutch' mutation on the production and stability of amyloid beta-protein.

https://arctichealth.org/en/permalink/ahliterature201872
Source
Biochem J. 1999 Jun 15;340 ( Pt 3):703-9
Publication Type
Article
Date
Jun-15-1999
Author
D J Watson
D J Selkoe
D B Teplow
Author Affiliation
Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Source
Biochem J. 1999 Jun 15;340 ( Pt 3):703-9
Date
Jun-15-1999
Language
English
Publication Type
Article
Keywords
Amino Acid Sequence
Amino Acid Substitution
Amyloid beta-Peptides - chemistry - genetics - metabolism
Amyloid beta-Protein Precursor - chemistry - genetics - metabolism
Amyloidosis - genetics
Cell Line
Cerebral Hemorrhage - genetics
Culture Media, Conditioned - chemistry - metabolism
Glutamic Acid - genetics - metabolism
Glutamine - genetics - metabolism
Humans
Molecular Sequence Data
Molecular Weight
Netherlands
Peptide Fragments - chemistry - metabolism
Precipitin Tests
Protein Processing, Post-Translational
Sequence Analysis
Sweden
Time Factors
Abstract
Hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D), is a cerebral amyloidosis characterized by prominent vascular deposits and fatal haemorrhages. The disorder is caused by a point mutation in codon 693 of the gene encoding the amyloid precursor protein (APP), resulting in a Glu-->Gln amino acid substitution at position 22 of the amyloid beta-protein (Abeta) region. The pathogenetic mechanisms of HCHWA-D are unknown but could involve alterations in the proteolytic processing of APP and in amyloid fibril formation. We examined Abeta production and stability by using cultured human embryonic kidney 293 cells stably expressing wild-type or 'Dutch' APP. Radiosequencing and quantitative immunoprecipitation experiments showed that cells expressing Dutch APP secreted increased quantities of Abeta peptides beginning at Asp1, and of truncated peptides beginning at Val18 and Phe19. The ratio of levels of 4 kDa (Abeta) to 3 kDa (p3) peptides remained constant due to co-ordinate decreases in other peptide species. Novel truncated or elongated peptides were not observed. Pulse-chase experiments showed that the Dutch mutation did not affect the stability of the Abeta or p3 populations. These results are consistent with a disease process in which the Dutch mutation results in the production of Abeta peptides with enhanced propensities for fibrillogenesis, leading to accelerated vascular deposition and disease.
Notes
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PubMed ID
10359654 View in PubMed
Less detail

Glucagon-like peptide-1 as a treatment option for type 2 diabetes and its role in restoring beta-cell mass.

https://arctichealth.org/en/permalink/ahliterature46990
Source
Diabetes Technol Ther. 2005 Aug;7(4):651-7
Publication Type
Article
Date
Aug-2005
Author
B. Gallwitz
Author Affiliation
Department of Medicine IV, Eberhard-Karls-University, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. baptist.gallwitz@med.uni-tuebingen.de
Source
Diabetes Technol Ther. 2005 Aug;7(4):651-7
Date
Aug-2005
Language
English
Publication Type
Article
Keywords
Amino Acid Sequence
Animals
Diabetes Mellitus, Type 2 - drug therapy
Glucagon - chemistry - therapeutic use
Glucagon-Like Peptide 1
Humans
Islets of Langerhans - drug effects - pathology
Mice
Models, Biological
Molecular Sequence Data
Peptide Fragments - chemistry - therapeutic use
Protein Precursors - chemistry - therapeutic use
Satiation
Abstract
The "incretin effect" describes the enhanced insulin response from orally ingested glucose compared with intravenous glucose leading to identical postprandial plasma glucose excursions. It makes up to 60% of the postprandial insulin secretion but is diminished in type 2 diabetes. Gastrointestinal hormones promoting the incretin effect are called incretins. Glucagon-like peptide- 1 (GLP-1) is an important incretin. In vitro and animal data have demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. The improvement of beta-cell function can be indirectly observed from the increased insulin secretory capacity of humans receiving GLP-1 or incretin mimetics that act like GLP-1. Furthermore, GLP-1 inhibits glucagon secretion and rarely causes hypoglycemia. It may represent an attractive therapeutic method for type 2 diabetes because of its multiple effects, including a slowing of gastric emptying and the simulation of satiety by acting as a transmitter in the CNS. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasable for routine therapy. Long-acting GLP-1 analogs (e.g., Liraglutide [Novo Nordisk, Copenhagen, Denmark]) and exenadin-4 (Exenatide [Eli Lilly, Indianapolis, IN]) that are resistant to degradation, called "incretin mimetics," are being investigated in clinical trials. Dipeptidyl peptidase IV inhibitors (e.g., Vildagliptin [Novartis, Basel, Switzerland]) that inhibit the enzyme responsible for incretin degradation are also under study.
PubMed ID
16120042 View in PubMed
Less detail

Identification of beta-secretase-like activity using a mass spectrometry-based assay system.

https://arctichealth.org/en/permalink/ahliterature199767
Source
Nat Biotechnol. 2000 Jan;18(1):66-70
Publication Type
Article
Date
Jan-2000
Author
F. Grüninger-Leitch
P. Berndt
H. Langen
P. Nelboeck
H. Döbeli
Author Affiliation
CNS Research, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Source
Nat Biotechnol. 2000 Jan;18(1):66-70
Date
Jan-2000
Language
English
Publication Type
Article
Keywords
Amino Acid Sequence
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor - genetics - metabolism
Animals
Aspartic Acid Endopeptidases - chemistry - metabolism
Cathepsin D - chemistry - metabolism
Cathepsin E - genetics - metabolism
Cell Extracts - chemistry
Cell Line
Ceramics
Endopeptidases
Humans
Metalloendopeptidases - metabolism
Mice
Microspheres
Molecular Sequence Data
Molecular Weight
Mutation - genetics
Pepstatins - metabolism
Peptide Fragments - chemistry - metabolism
Rats
Recombinant Fusion Proteins - chemistry - metabolism
Reproducibility of Results
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - methods
Substrate Specificity
Sweden
Transfection
Abstract
We describe an assay system for the identification of site-specific proteases. The assay is based on a protein substrate that is immobilized on ceramic beads. After incubation with cell homogenates, the beads are washed and digested with endoproteinase Lys-C to liberate a defined set of peptides. The peptide fragments are identified by mass spectrometry. The assay was used to screen for beta-secretase, the protease that cleaves amyloid precursor protein (APP) at the beta-site. Cathepsin D was identified as the enzyme responsible for beta-secretase-like activity in two cell lines. Subsequent analysis of the related aspartic protease, cathepsin E, revealed almost identical cleavage specificity. Both enzymes are efficient in cleaving Swedish mutant APP at the beta-site but show almost no reactivity with wild-type APP. Treatment of cell lines with pepstatin inhibited the production of amyloid peptide (Abeta) when they were transfected with a construct bearing the Swedish APP mutant. However, when the cells were transfected with wild-type APP, the generation of Abeta was increased. This suggests that more than one enzyme is capable of generating Abeta in vivo and that an aspartic protease is involved in the processing of Swedish mutant APP.
PubMed ID
10625394 View in PubMed
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