scholarly journals Reengineering biocatalysts: Computational redesign of chondroitinase ABC improves efficacy and stability

2020 ◽  
Vol 6 (34) ◽  
pp. eabc6378
Author(s):  
Marian H. Hettiaratchi ◽  
Matthew J. O’Meara ◽  
Teresa R. O’Meara ◽  
Andrew J. Pickering ◽  
Nitzan Letko-Khait ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Amino Acid ◽  
Wild Type ◽  
Chondroitinase Abc ◽  
Cns Regeneration ◽  
Src Homology 3 ◽  
Src Homology ◽  
Binding Peptides ◽  
Critical Challenge

Maintaining biocatalyst stability and activity is a critical challenge. Chondroitinase ABC (ChABC) has shown promise in central nervous system (CNS) regeneration, yet its therapeutic utility is severely limited by instability. We computationally reengineered ChABC by introducing 37, 55, and 92 amino acid changes using consensus design and forcefield-based optimization. All mutants were more stable than wild-type ChABC with increased aggregation temperatures between 4° and 8°C. Only ChABC with 37 mutations (ChABC-37) was more active and had a 6.5 times greater half-life than wild-type ChABC, increasing to 106 hours (4.4 days) from only 16.8 hours. ChABC-37, expressed as a fusion protein with Src homology 3 (ChABC-37-SH3), was active for 7 days when released from a hydrogel modified with SH3-binding peptides. This study demonstrates the broad opportunity to improve biocatalysts through computational engineering and sets the stage for future testing of this substantially improved protein in the treatment of debilitating CNS injuries.

Vasopressin analogues with effect on central nervous system: Synthesis and biological properties

1983 ◽  
Vol 48 (10) ◽  
pp. 2862-2873 ◽  
Author(s):  
František Brtník ◽  
Ivan Krejčí ◽  
Běla Kupková ◽  
Pavel Hrbas ◽  
Jana Škopková ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Amino Acid ◽  
Passive Avoidance ◽  
Biological Properties ◽  
Passive Avoidance Test ◽  
System Synthesis ◽  
Avoidance Test ◽  
Vasopressin Analogues

Synthesis of four vasopressin analogues which do not contain the glycinamine residue in position 9 and have a basic non-coded amino acid in position 8 is described. All the analogues exhibit very low endocrine activities and are effective in the passive avoidance test.

Inflammatory Chemokines Expression Variations and Their Receptors in APP/PS1 Mice

2021 ◽  
pp. 1-10
Author(s):  
Adrián Jorda ◽  
Martin Aldasoro ◽  
Constanza Aldasoro ◽  
Soraya L. Valles
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Chemokine Receptors ◽  
Presenilin 1 ◽  
Wild Type ◽  
Rt Pcr ◽  
New Strategy ◽  
Inflammatory Chemokines ◽  
Inflammatory Changes ◽  
Old Mice

Background: In Alzheimer’s disease (AD), an increase in inflammation is distinctive. Amyloid precursor protein plus presenilin-1 (APP/PS1 mice) is a model for this illness. Chemokines secreted by central nervous system (CNS) cells could play multiple important roles in AD. Data looking for the chemokines involved in inflammatory mechanisms are lacking. To understand the changes that occur in the inflammation process in AD, it is necessary to improve strategies to act on specific inflammatory targets. Objective: Chemokines and their receptors involved in phagocytosis, demyelination, chemotaxis, and coagulation were the objective of our study. Methods: Female APPswe/PS1 double-transgenic mice (B6C3-Tg) were used and cortex brain from 20–22-month-old mice obtained and used to quantify chemokines and chemokine receptors expression using RT-PCR technique. Results: Significant inflammatory changes were detected in APP/PS1 compared to wild type mice. CCR1, CCR3, CCR4, and CCR9 were elevated, and CCR2 were decreased compared with wild type mice. Their ligands CCL7, CCL11, CCL17, CCL22, CCL25, and CXCL4 showed an increase expression; however, changes were not observed in CCL2 in APP/PS1 compared to wild type mice. Conclusion: This change in expression could explain the differences between AD patients and elderly people without this illness. This would provide a new strategy for the treatment of AD, with the possibility to act in specific inflammatory targets.

scholarly journals Amino acid sequence of the encephalitogenic basic protein from human myelin

1971 ◽  
Vol 123 (1) ◽  
pp. 57-67 ◽  
Author(s):  
P. R. Carnegie
Keyword(s):  
Amino Acids ◽  
Central Nervous System ◽  
Nervous System ◽  
Amino Acid ◽  
Basic Protein ◽  
Structure And Function ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
And Function ◽  
Experimental Autoimmune

Myelin from the central nervous system contains an unusual basic protein, which can induce experimental autoimmune encephalomyelitis. The basic protein from human brain was digested with trypsin and other enzymes and the sequence of the 170 amino acids was determined. The localization of the encephalitogenic determinants was described. Possible roles for the protein in the structure and function of myelin are discussed.

scholarly journals The oligodendrocyte-myelin glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate.

1990 ◽  
Vol 110 (2) ◽  
pp. 471-479 ◽  
Author(s):  
D D Mikol ◽  
J R Gulcher ◽  
K Stefansson
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Amino Acid ◽  
Terminal Segment ◽  
Platelet Glycoprotein ◽  
Glycoprotein Ib ◽  
Attachment Sites ◽  
Initial Adhesion ◽  
The Central Nervous System ◽  
Oligodendrocyte Myelin Glycoprotein

The complete primary structure of the human oligodendrocyte-myelin glycoprotein (OMgp), a glycophospholipid-linked membrane protein of oligodendrocytes and central nervous system myelin, has been determined. The deduced amino acid sequence predicts a polypeptide of 433 amino acids which includes a 17-amino acid leader sequence. OMgp consists of four domains: (a) a short cysteine-rich motif at the NH2 terminus; (b) a series of tandem leucine-rich repeats (LRs) present in several other proteins where they may play roles in adhesion; (c) a serine/threonine-rich region that contains probable attachment sites for O-linked carbohydrates; and (d) a hydrophobic COOH-terminal segment that is likely to be cleaved concomitant with the attachment of lipid during biosynthesis of OMgp. OMgp shares the first three of its four domains with the platelet glycoprotein Ib, which is responsible for the initial adhesion of platelets to the exposed subendothelium during hemostasis. Together with glycoprotein Ib and several other proteins, OMgp belongs to a family of proteins that contain both an NH2-terminal cysteine-rich motif and an adjacent series of LRs. In addition, we report that a subpopulation of OMgp molecules contains the HNK-1 carbohydrate, which has been shown to mediate interactions among cells in the central nervous system.

Neurogenic and antineurogenic effects from modifications at the Notch locus

Development ◽  
1990 ◽  
Vol 109 (1) ◽  
pp. 167-175 ◽  
Author(s):  
J. Palka ◽  
M. Schubiger ◽  
H. Schwaninger
Keyword(s):  
Nervous System ◽  
Amino Acid ◽  
Distinctive Feature ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Significant Extent ◽  
Notch Protein ◽  
Notch Locus ◽  
Mother Cells

The best studied mutations at the Notch locus produce a neurogenic phenotype, with a massive overgrowth of the nervous system at the expense of epidermis. We report here that, in the development of the adult peripheral nervous system, the Abruptex alleles of Notch have the opposite phenotype, namely an underproduction of sensory organs or sensilla. This arises primarily not from an arrest of the lineages that produce sensilla, from the degeneration of sensillar cells, or from the transformation into neurons of cells that normally secrete the cuticular components of a sensillum (as can happen in Notch alleles). Rather, our evidence argues strongly that the sensillar mother cells never form. This implies that the Notch protein plays a role in the process that first generates a difference between sensillar mother cells and ordinary epidermal cells. The number of sensilla formed on the wing of flies carrying multiple doses of Notch+ is virtually the same as that of wild type, i.e. the Abruptex phenotype is not reproduced to any significant extent. This suggests that the single amino acid substitutions that occur in Abruptex mutants confer on the protein some functionally distinctive feature, possibly more powerful intermolecular binding or altered stability.

Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins

Cell ◽  
1994 ◽  
Vol 76 (1) ◽  
pp. 117-129 ◽  
Author(s):  
David Westaway ◽  
Stephen J. DeArmond ◽  
Juliana Cayetano-Canlas ◽  
Darlene Groth ◽  
Dallas Foster ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Central Nervous System ◽  
Nervous System ◽  
Transgenic Mice ◽  
Peripheral Nerves ◽  
Prion Proteins ◽  
Wild Type ◽  
The Central Nervous System
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