A computational module assembled from different protease family motifs identifies PI PLC from Bacillus cereus as a putative prolyl peptidase with a serine protease scaffold

Proteolytic enzymes have evolved several mechanisms to cleave peptide bonds. These distinct types have been systematically categorized in the MEROPS database. While a BLAST search on these proteases identifies homologous proteins, sequence alignment methods often fail to identify relationships arisi...

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Veröffentlicht in:PloS one 2013-08, Vol.8 (8), p.e70923-e70923
Hauptverfasser: Rendón-Ramírez, Adela, Shukla, Manish, Oda, Masataka, Chakraborty, Sandeep, Minda, Renu, Dandekar, Abhaya M, Ásgeirsson, Bjarni, Goñi, Félix M, Rao, Basuthkar J
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container_title PloS one
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creator Rendón-Ramírez, Adela
Shukla, Manish
Oda, Masataka
Chakraborty, Sandeep
Minda, Renu
Dandekar, Abhaya M
Ásgeirsson, Bjarni
Goñi, Félix M
Rao, Basuthkar J
description Proteolytic enzymes have evolved several mechanisms to cleave peptide bonds. These distinct types have been systematically categorized in the MEROPS database. While a BLAST search on these proteases identifies homologous proteins, sequence alignment methods often fail to identify relationships arising from convergent evolution, exon shuffling, and modular reuse of catalytic units. We have previously established a computational method to detect functions in proteins based on the spatial and electrostatic properties of the catalytic residues (CLASP). CLASP identified a promiscuous serine protease scaffold in alkaline phosphatases (AP) and a scaffold recognizing a β-lactam (imipenem) in a cold-active Vibrio AP. Subsequently, we defined a methodology to quantify promiscuous activities in a wide range of proteins. Here, we assemble a module which encapsulates the multifarious motifs used by protease families listed in the MEROPS database. Since APs and proteases are an integral component of outer membrane vesicles (OMV), we sought to query other OMV proteins, like phospholipase C (PLC), using this search module. Our analysis indicated that phosphoinositide-specific PLC from Bacillus cereus is a serine protease. This was validated by protease assays, mass spectrometry and by inhibition of the native phospholipase activity of PI-PLC by the well-known serine protease inhibitor AEBSF (IC50 = 0.018 mM). Edman degradation analysis linked the specificity of the protease activity to a proline in the amino terminal, suggesting that the PI-PLC is a prolyl peptidase. Thus, we propose a computational method of extending protein families based on the spatial and electrostatic congruence of active site residues.
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These distinct types have been systematically categorized in the MEROPS database. While a BLAST search on these proteases identifies homologous proteins, sequence alignment methods often fail to identify relationships arising from convergent evolution, exon shuffling, and modular reuse of catalytic units. We have previously established a computational method to detect functions in proteins based on the spatial and electrostatic properties of the catalytic residues (CLASP). CLASP identified a promiscuous serine protease scaffold in alkaline phosphatases (AP) and a scaffold recognizing a β-lactam (imipenem) in a cold-active Vibrio AP. Subsequently, we defined a methodology to quantify promiscuous activities in a wide range of proteins. Here, we assemble a module which encapsulates the multifarious motifs used by protease families listed in the MEROPS database. Since APs and proteases are an integral component of outer membrane vesicles (OMV), we sought to query other OMV proteins, like phospholipase C (PLC), using this search module. Our analysis indicated that phosphoinositide-specific PLC from Bacillus cereus is a serine protease. This was validated by protease assays, mass spectrometry and by inhibition of the native phospholipase activity of PI-PLC by the well-known serine protease inhibitor AEBSF (IC50 = 0.018 mM). Edman degradation analysis linked the specificity of the protease activity to a proline in the amino terminal, suggesting that the PI-PLC is a prolyl peptidase. Thus, we propose a computational method of extending protein families based on the spatial and electrostatic congruence of active site residues.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23940667</pmid><doi>10.1371/journal.pone.0070923</doi><tpages>e70923</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
ispartof PloS one, 2013-08, Vol.8 (8), p.e70923-e70923
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_1430247327
source MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry
subjects Amides
Amino Acid Motifs
Aspartic proteases
Bacillus cereus
Bacillus cereus - enzymology
Bacterial Proteins - chemistry
Beta lactamases
Biochemistry
Biology
Catalytic converters
Catalytic Domain
Chemistry
Clostridium perfringens
Computation
Computer applications
Computer Science
Computer Simulation
Data bases
Edman degradation
Electrostatic properties
Enzymes
Evolution
Evolution (Biology)
Fluorides
Homology
Identification methods
Imipenem
Lactams
Mass spectrometry
Mass spectroscopy
Membrane vesicles
Models, Molecular
Modular units
Nucleotide sequence
Peptidase
Peptides
Phosphatases
Phosphoinositide Phospholipase C - chemistry
Phospholipase
Phospholipase C
Proline
Protease
Protease inhibitors
Proteases
Protein families
Proteins
Proteolysis
Proteolytic enzymes
Residues
Serine
Serine Endopeptidases - chemistry
Serine proteinase
Signal transduction
Spatial discrimination
Thrombin
Vibrio
Water-borne diseases
Waterborne diseases
title A computational module assembled from different protease family motifs identifies PI PLC from Bacillus cereus as a putative prolyl peptidase with a serine protease scaffold
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