Substrate-driven mapping of the degradome by comparison of sequence logos.

Sequence logos are frequently used to illustrate substrate preferences and specificity of proteases. Here, we employed the compiled substrates of the MEROPS database to introduce a novel metric for comparison of protease substrate preferences. The constructed similarity matrix of 62 proteases can be...

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Autores principales:	Julian E Fuchs, Susanne von Grafenstein, Roland G Huber, Christian Kramer, Klaus R Liedl
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0c61c0e7a9f04c15a3da1ed5cdcf1f7d
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spelling	oai:doaj.org-article:0c61c0e7a9f04c15a3da1ed5cdcf1f7d2021-11-18T05:53:22ZSubstrate-driven mapping of the degradome by comparison of sequence logos.1553-734X1553-735810.1371/journal.pcbi.1003353https://doaj.org/article/0c61c0e7a9f04c15a3da1ed5cdcf1f7d2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24244149/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Sequence logos are frequently used to illustrate substrate preferences and specificity of proteases. Here, we employed the compiled substrates of the MEROPS database to introduce a novel metric for comparison of protease substrate preferences. The constructed similarity matrix of 62 proteases can be used to intuitively visualize similarities in protease substrate readout via principal component analysis and construction of protease specificity trees. Since our new metric is solely based on substrate data, we can engraft the protease tree including proteolytic enzymes of different evolutionary origin. Thereby, our analyses confirm pronounced overlaps in substrate recognition not only between proteases closely related on sequence basis but also between proteolytic enzymes of different evolutionary origin and catalytic type. To illustrate the applicability of our approach we analyze the distribution of targets of small molecules from the ChEMBL database in our substrate-based protease specificity trees. We observe a striking clustering of annotated targets in tree branches even though these grouped targets do not necessarily share similarity on protein sequence level. This highlights the value and applicability of knowledge acquired from peptide substrates in drug design of small molecules, e.g., for the prediction of off-target effects or drug repurposing. Consequently, our similarity metric allows to map the degradome and its associated drug target network via comparison of known substrate peptides. The substrate-driven view of protein-protein interfaces is not limited to the field of proteases but can be applied to any target class where a sufficient amount of known substrate data is available.Julian E FuchsSusanne von GrafensteinRoland G HuberChristian KramerKlaus R LiedlPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 9, Iss 11, p e1003353 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Julian E Fuchs Susanne von Grafenstein Roland G Huber Christian Kramer Klaus R Liedl Substrate-driven mapping of the degradome by comparison of sequence logos.
description	Sequence logos are frequently used to illustrate substrate preferences and specificity of proteases. Here, we employed the compiled substrates of the MEROPS database to introduce a novel metric for comparison of protease substrate preferences. The constructed similarity matrix of 62 proteases can be used to intuitively visualize similarities in protease substrate readout via principal component analysis and construction of protease specificity trees. Since our new metric is solely based on substrate data, we can engraft the protease tree including proteolytic enzymes of different evolutionary origin. Thereby, our analyses confirm pronounced overlaps in substrate recognition not only between proteases closely related on sequence basis but also between proteolytic enzymes of different evolutionary origin and catalytic type. To illustrate the applicability of our approach we analyze the distribution of targets of small molecules from the ChEMBL database in our substrate-based protease specificity trees. We observe a striking clustering of annotated targets in tree branches even though these grouped targets do not necessarily share similarity on protein sequence level. This highlights the value and applicability of knowledge acquired from peptide substrates in drug design of small molecules, e.g., for the prediction of off-target effects or drug repurposing. Consequently, our similarity metric allows to map the degradome and its associated drug target network via comparison of known substrate peptides. The substrate-driven view of protein-protein interfaces is not limited to the field of proteases but can be applied to any target class where a sufficient amount of known substrate data is available.
format	article
author	Julian E Fuchs Susanne von Grafenstein Roland G Huber Christian Kramer Klaus R Liedl
author_facet	Julian E Fuchs Susanne von Grafenstein Roland G Huber Christian Kramer Klaus R Liedl
author_sort	Julian E Fuchs
title	Substrate-driven mapping of the degradome by comparison of sequence logos.
title_short	Substrate-driven mapping of the degradome by comparison of sequence logos.
title_full	Substrate-driven mapping of the degradome by comparison of sequence logos.
title_fullStr	Substrate-driven mapping of the degradome by comparison of sequence logos.
title_full_unstemmed	Substrate-driven mapping of the degradome by comparison of sequence logos.
title_sort	substrate-driven mapping of the degradome by comparison of sequence logos.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/0c61c0e7a9f04c15a3da1ed5cdcf1f7d
work_keys_str_mv	AT julianefuchs substratedrivenmappingofthedegradomebycomparisonofsequencelogos AT susannevongrafenstein substratedrivenmappingofthedegradomebycomparisonofsequencelogos AT rolandghuber substratedrivenmappingofthedegradomebycomparisonofsequencelogos AT christiankramer substratedrivenmappingofthedegradomebycomparisonofsequencelogos AT klausrliedl substratedrivenmappingofthedegradomebycomparisonofsequencelogos
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Substrate-driven mapping of the degradome by comparison of sequence logos.

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