Document Detail


Folding competence of N-terminally truncated forms of human procathepsin B.
MedLine Citation:
PMID:  15657038     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Besides acting as an inhibitor, the propeptide of human cathepsin B exerts an important auxiliary function as a chaperone in promoting correct protein folding. To explore the ability of N-terminally truncated forms of procathepsin B to fold into enzymatically active proteins, we produced procathepsin B variants progressively lacking N-terminal structural elements in baculovirus-infected insect cells. N-terminal truncation of the propeptide by up to 22 amino acids did not impair the production of activable procathepsin B. Secreted forms lacking the first 20, 21, or 22 amino acids spontaneously generated mature cathepsin B through autocatalytic processing, demonstrating that the first alpha-helix (Asp11-Arg20) is necessary for efficient inhibition of the enzyme by its propeptide. In contrast, proenzymes lacking the N-terminal part including the first beta-sheet (Trp24-Ala26) of the propeptide or containing an amino acid mutation directly preceding this beta-sheet were no longer properly folded. This shows that interactions between Trp24 of the propeptide and Tyr183, Tyr188, and Phe180 of the mature enzyme are important for stabilization and essential for procathepsin B folding. Thus, proenzyme forms missing more than the N-terminal 22 amino acids of the propeptide (notably truncated cathepsin B produced by the mRNA splice variant lacking exons 2 and 3, resulting in a propeptide shortened by 34 amino acids) are devoid of proteolytic activity because they cannot fold correctly. Thus, any pathophysiological involvement of truncated cathepsin B must be ascribed to properties other than proteolysis.
Authors:
Kathrin Müntener; Anna Willimann; Roman Zwicky; Barbara Svoboda; Lukas Mach; Antonio Baici
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-01-18
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  280     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-03-21     Completed Date:  2005-04-21     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11973-80     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cathepsin B / chemistry*,  metabolism
Cytosol / enzymology
Enzyme Precursors / chemistry*
Glycosylation
Humans
Protein Folding*
Protein Structure, Secondary
Recombinant Proteins / chemistry
Spodoptera
Chemical
Reg. No./Substance:
0/Enzyme Precursors; 0/Recombinant Proteins; EC 3.4.22.-/procathepsin B; EC 3.4.22.1/Cathepsin B

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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