Role of amino acid sequences flanking dibasic cleavage sites in precursor proteolytic processing. The importance of the first residue C-terminal of the cleavage site

Détails

ID Serval
serval:BIB_D509D631C856
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Role of amino acid sequences flanking dibasic cleavage sites in precursor proteolytic processing. The importance of the first residue C-terminal of the cleavage site
Périodique
European Journal of Biochemistry
Auteur(s)
Rholam  M., Brakch  N., Germain  D., Thomas  D. Y., Fahy  C., Boussetta  H., Boileau  G., Cohen  P.
ISSN
0014-2956 (Print)
Statut éditorial
Publié
Date de publication
02/1995
Volume
227
Numéro
3
Pages
707-14
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Feb 1
Résumé
The amino acid sequences flanking 352 dibasic moieties contained in 83 prohormones and pro-proteins listed in a database were examined. Frequency calculations on the occurrence of given residues at positions P6 to P'4 allowed us to delineate a number of features which might be in part responsible for the in vivo discrimination between cleaved and uncleaved dibasic sites. These include the following: amino acids at these positions were characterized by a large variability in composition and properties; no major contribution of a given precursor subsite to endoprotease specificity was observed; some amino acid residues appeared to occupy preferentially certain precursor subsites (for instance, Met in P6 and P3, Asp and Ala in P'1, Pro in P6, Gly in P3 and P'2 etc.) whereas some others appeared to be excluded. Most amino acid residues occupying the P'1 position in these precursor cleavage sites were tolerated. But the beta-carbon branched side chain residues (Thr, Val, Leu, Ile) and Pro, Cys, Met and Trp were either totally excluded or poorly represented, suggesting that they might be unfavourable to cleavage. The biological relevance of these observations to the efficacy of dibasic cleavage by model propeptide convertases was in vitro tested using both pro-ocytocin convertase and Kex2 protease action on a series of pro-ocytocin related synthetic substrates reproducing the Pro7-->Leu15 sequence of the precursor in which the Ala13 residue (P'1 in the LysArg-Ala motif) was replaced by various amino acid residues. A good correlation was obtained on this model system indicating that P'1 residue of precursor dibasic processing sites is an important feature and may play the role of anchoring motif to S'1 convertase subsite. We tentatively propose that the present database, and the corresponding model, may be used for further investigation of dibasic endoproteolytic processing of propeptides and pro-proteins.
Mots-clé
Amino Acid Sequence Binding Sites Databases, Factual Endopeptidases/metabolism Hormones/chemistry/metabolism Models, Biological Molecular Sequence Data Oligopeptides/chemistry/metabolism Peptide Hydrolases/*metabolism *Proprotein Convertases Protein Precursors/*chemistry/*metabolism *Protein Processing, Post-Translational *Saccharomyces cerevisiae Proteins Substrate Specificity Subtilisins/metabolism
Pubmed
Web of science
Création de la notice
28/01/2008 11:35
Dernière modification de la notice
20/08/2019 16:54
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