Identification of proprotein convertase substrates using genome-wide expression correlation analysis

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dc.contributor.author Turpeinen, Hannu -
dc.contributor.author Kukkurainen, Sampo -
dc.contributor.author Pulkkinen, Kati -
dc.contributor.author Kauppila, Timo -
dc.contributor.author Ojala, Kalle -
dc.contributor.author Hytönen, Vesa P -
dc.contributor.author Pesu, Marko -
dc.date.accessioned 2012-06-17T20:15:19Z
dc.date.available 2012-06-16 22:15:36 -
dc.date.available 2012-06-17T20:15:19Z
dc.date.issued 2011 -
dc.identifier.issn 1471-2164 -
dc.identifier.uri http://tampub.uta.fi/handle/10024/66072
dc.description BioMed central open access   -
dc.description.abstract Background Subtilisin/kexin-like proprotein convertase (PCSK) enzymes have important regulatory function in a wide variety of biological processes. PCSKs proteolytically process at a target sequence that contains basic amino acids arginine and lysine, which results in functional maturation of the target protein. In vitro assays have showed significant biochemical redundancy between the seven family members, but the phenotypes of PCSK deficient mice and patients carrying an inactive PCSK allele argue for a specific biological function. Modeling the structures of individual PCSK enzymes has offered little insights into the specificity determinants. However, previous studies have shown that there can be a coordinated expression between a PCSK and its target molecule. Here, we have surveyed the putative PCSK target proteins using genome-wide expression correlation analysis and cleavage site prediction algorithms. Results We first performed a gene expression correlation analysis over the whole genome for all PCSK enzymes. PCSKs were found to cluster differently based on the strength of correlations. The screen for putative PCSK target proteins showed a significant enrichment (p-values from 1.2e-4 to < 1.0e-10) of putative targets among the most positively correlating genes for most PCSKs. Interestingly, there was no enrichment in putative targets among the genes that correlated positively with the biologically redundant PCSK7, whereas PCSK5 showed an inverse correlation. PCSKs also showed a highly variable degree of shared target genes that were identified by expression correlation and cleavage site prediction. Multiple alignments were used to evaluate the putative targets to pinpoint the important residues for the substrate recognition. Finally, we validated our approach and identified biochemically PAPPA1 and ADAMTS6 as novel targets for FURIN proteolytic activity. Conclusions Most PCSK enzymes display strong positive expression correlation with predicted target proteins in our genome-wide analysis. We also show that expression correlation screen combined with a cleavage site-prediction analysis can be used to identify novel bona fide target molecules for PCSKs. Exploring the positively correlating genes can thus offer additional insights into the biology of proprotein convertases. -
dc.language.iso en -
dc.title Identification of proprotein convertase substrates using genome-wide expression correlation analysis -
dc.type fi=Artikkeli aikakauslehdessä | en=Journal article| -
dc.identifier.urn urn:nbn:uta-3-847 -
dc.identifier.doi 10.1186/1471-2164-12-618 -
dc.type.version fi=Kustantajan versio | en=Publisher's version| -
dc.subject.okm fi=Lääketieteen bioteknologia | en=Medical biotechnology| -
dc.administrativeunit fi=Biolääketieteellisen teknologian yksikkö | en=Institute of Biomedical Technology| -
dc.journal.title BMC Genomics -
dc.journal.volume 12 -
dc.journal.number 618 -
dc.journal.volumepagerange 1-10 -
dc.oldstats 50 -

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