Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.

Activity regulated neurotransmission shapes the computational properties of a neuron and involves the concerted action of many proteins. Classical, intuitive working models often assign specific proteins to specific steps in such complex cellular processes, whereas modern systems theories emphasize...

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Autores principales:	L Niels Cornelisse, Evgeni Tsivtsivadze, Marieke Meijer, Tjeerd M H Dijkstra, Tom Heskes, Matthijs Verhage
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/eb8a63eabcad48f3bd8a55dd4272468d
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spelling	oai:doaj.org-article:eb8a63eabcad48f3bd8a55dd4272468d2021-11-18T05:51:26ZMolecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.1553-734X1553-735810.1371/journal.pcbi.1002450https://doaj.org/article/eb8a63eabcad48f3bd8a55dd4272468d2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22496630/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Activity regulated neurotransmission shapes the computational properties of a neuron and involves the concerted action of many proteins. Classical, intuitive working models often assign specific proteins to specific steps in such complex cellular processes, whereas modern systems theories emphasize more integrated functions of proteins. To test how often synaptic proteins participate in multiple steps in neurotransmission we present a novel probabilistic method to analyze complex functional data from genetic perturbation studies on neuronal secretion. Our method uses a mixture of probabilistic principal component analyzers to cluster genetic perturbations on two distinct steps in synaptic secretion, vesicle priming and fusion, and accounts for the poor standardization between different studies. Clustering data from 121 perturbations revealed that different perturbations of a given protein are often assigned to different steps in the release process. Furthermore, vesicle priming and fusion are inversely correlated for most of those perturbations where a specific protein domain was mutated to create a gain-of-function variant. Finally, two different modes of vesicle release, spontaneous and action potential evoked release, were affected similarly by most perturbations. This data suggests that the presynaptic protein network has evolved as a highly integrated supramolecular machine, which is responsible for both spontaneous and activity induced release, with a group of core proteins using different domains to act on multiple steps in the release process.L Niels CornelisseEvgeni TsivtsivadzeMarieke MeijerTjeerd M H DijkstraTom HeskesMatthijs VerhagePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 8, Iss 4, p e1002450 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 L Niels Cornelisse Evgeni Tsivtsivadze Marieke Meijer Tjeerd M H Dijkstra Tom Heskes Matthijs Verhage Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.
description	Activity regulated neurotransmission shapes the computational properties of a neuron and involves the concerted action of many proteins. Classical, intuitive working models often assign specific proteins to specific steps in such complex cellular processes, whereas modern systems theories emphasize more integrated functions of proteins. To test how often synaptic proteins participate in multiple steps in neurotransmission we present a novel probabilistic method to analyze complex functional data from genetic perturbation studies on neuronal secretion. Our method uses a mixture of probabilistic principal component analyzers to cluster genetic perturbations on two distinct steps in synaptic secretion, vesicle priming and fusion, and accounts for the poor standardization between different studies. Clustering data from 121 perturbations revealed that different perturbations of a given protein are often assigned to different steps in the release process. Furthermore, vesicle priming and fusion are inversely correlated for most of those perturbations where a specific protein domain was mutated to create a gain-of-function variant. Finally, two different modes of vesicle release, spontaneous and action potential evoked release, were affected similarly by most perturbations. This data suggests that the presynaptic protein network has evolved as a highly integrated supramolecular machine, which is responsible for both spontaneous and activity induced release, with a group of core proteins using different domains to act on multiple steps in the release process.
format	article
author	L Niels Cornelisse Evgeni Tsivtsivadze Marieke Meijer Tjeerd M H Dijkstra Tom Heskes Matthijs Verhage
author_facet	L Niels Cornelisse Evgeni Tsivtsivadze Marieke Meijer Tjeerd M H Dijkstra Tom Heskes Matthijs Verhage
author_sort	L Niels Cornelisse
title	Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.
title_short	Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.
title_full	Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.
title_fullStr	Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.
title_full_unstemmed	Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.
title_sort	molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/eb8a63eabcad48f3bd8a55dd4272468d
work_keys_str_mv	AT lnielscornelisse molecularmachinesinthesynapseoverlappingproteinsetscontroldistinctstepsinneurosecretion AT evgenitsivtsivadze molecularmachinesinthesynapseoverlappingproteinsetscontroldistinctstepsinneurosecretion AT mariekemeijer molecularmachinesinthesynapseoverlappingproteinsetscontroldistinctstepsinneurosecretion AT tjeerdmhdijkstra molecularmachinesinthesynapseoverlappingproteinsetscontroldistinctstepsinneurosecretion AT tomheskes molecularmachinesinthesynapseoverlappingproteinsetscontroldistinctstepsinneurosecretion AT matthijsverhage molecularmachinesinthesynapseoverlappingproteinsetscontroldistinctstepsinneurosecretion
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Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion.

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