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Published on: June 6, 2020
Identification of proprotein convertase substrates using genome-wide expression correlation analysis.
Hannu Turpeinen1, Sampo Kukkurainen, Kati Pulkkinen
1Immunoregulation, Institute of Biomedical Technology, FI-33014 University of Tampere, Finland.
BMC Genomics
|December 22, 2011
Summary
Proprotein convertase subtilisin/kexin (PCSK) enzymes target proteins with basic amino acids. This study used expression correlation and cleavage site prediction to identify novel PCSK targets, revealing PAPPA1 and ADAMTS6 for FURIN.
Area of Science:
- Biochemistry
- Molecular Biology
- Genomics
Background:
- Subtilisin/kexin-like proprotein convertase (PCSK) enzymes regulate biological processes by cleaving target proteins containing basic amino acids.
- Despite in vitro redundancy, PCSK deficiency phenotypes suggest specific functions, but structural modeling offers limited insight into specificity.
- Coordinated expression between PCSKs and their targets has been previously observed.
Purpose of the Study:
- To identify novel proprotein convertase subtilisin/kexin (PCSK) target proteins using genome-wide expression correlation and cleavage site prediction.
- To investigate the specificity determinants of PCSK enzymes by analyzing expression patterns and substrate recognition residues.
- To validate the combined approach for identifying bona fide PCSK targets.
Main Methods:
- Genome-wide gene expression correlation analysis was performed for all PCSK enzymes.
- Cleavage site prediction algorithms were employed to identify potential target sequences.
- Multiple sequence alignments were used to evaluate putative targets and pinpoint key substrate recognition residues.
- Novel targets were biochemically validated.
Main Results:
- Significant enrichment of putative PCSK targets was found among positively correlating genes for most PCSKs, with notable exceptions for PCSK7 and PCSK5.
- Expression correlation and cleavage site prediction identified a variable degree of shared target genes across PCSKs.
- PAPPA1 and ADAMTS6 were identified as novel biochemical targets of FURIN.
- The study identified PAPPA1 and ADAMTS6 as novel targets for FURIN proteolytic activity.
Conclusions:
- Most PCSK enzymes exhibit strong positive expression correlation with predicted target proteins.
- Combining expression correlation with cleavage site prediction is an effective strategy for identifying novel PCSK targets.
- Analyzing positively correlating genes provides valuable insights into the biology of proprotein convertases.
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