Deconstruction of Neurotrypsin Reveals a Multi-factorially Regulated Activity Affecting Myotube Formation and Neuronal Excitability.
Agrin signaling
Neuromuscular junction
Neurotrypsin
Proteolytic regulation
Serine protease
Synapses
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Dec 2022
Dec 2022
Historique:
received:
03
06
2022
accepted:
21
09
2022
pubmed:
6
10
2022
medline:
2
11
2022
entrez:
5
10
2022
Statut:
ppublish
Résumé
Neurotrypsin (NT) is a highly specific nervous system multi-domain serine protease best known for its selective processing of the potent synaptic organizer agrin. Its enzymatic activity is thought to influence processes of synaptic plasticity, with its deregulation causing accelerated neuromuscular junction (NMJ) degeneration or contributing to forms of mental retardation. These biological effects are likely to stem from NT-based regulation of agrin signaling. However, dissecting the exact biological implications of NT-agrin interplay is difficult, due to the scarce molecular detail regarding NT activity and NT-agrin interactions. We developed a strategy to reliably produce and purify a catalytically competent engineered variant of NT called "NT-mini" and a library of C-terminal agrin fragments, with which we performed a thorough biochemical and biophysical characterization of NT enzyme functionality. We studied the regulatory effects of calcium ions and heparin, identified NT's heparin-binding domain, and discovered how zinc ions induce modulation of enzymatic activity. Additionally, we investigated myotube differentiation and hippocampal neuron excitability, evidencing a dose-dependent increase in neuronal activity alongside a negative impact on myoblast fusion when using the active NT enzyme. Collectively, our results provide in vitro and cellular foundations to unravel the molecular underpinnings and biological significance of NT-agrin interactions.
Identifiants
pubmed: 36197591
doi: 10.1007/s12035-022-03056-2
pii: 10.1007/s12035-022-03056-2
pmc: PMC9616769
doi:
Substances chimiques
Agrin
0
neurotrypsin
EC 3.4.21.-
Heparin
9005-49-6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7466-7485Subventions
Organisme : Fondazione Cariplo
ID : 2014-0881
Organisme : Giovanni Armenise-Harvard Foundation
ID : CDA 2013
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : Rita Levi-Montalcini Award
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : Dipartimenti di Eccellenza 2018-2022
Organisme : EMBO
ID : Short-term fellowship #7677
Organisme : Horizon 2020 Framework Programme
ID : Human Brain Project SGA3
Organisme : Horizon 2020 Framework Programme
ID : Grant Agreement No. 945539
Informations de copyright
© 2022. The Author(s).
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