The residual pro-part of cathepsin C fulfills the criteria required for an intramolecular chaperone in folding and stabilizing the human proenzyme.


Abstract

The 13.5 kDa N-terminal part of the propeptide remains associated with mature cathepsin C after proteolytic activation and excision of the activation peptide. This residual pro-part, isolated from the recombinant enzyme, folds spontaneously and rapidly to a stable, compact monomer with secondary structure and stable tertiary interactions. Folding and unfolding kinetics of the residual pro-part with intact disulfides are complex, and accumulation of transient intermediates is observed. The cleaved form of the pro-part isolated from natural human cathepsin C also folds, suggesting that the intact form comprises two folding domains. The linkages of the two disulfide bridges have been established as 30-118 and 54-136 for the native enzyme. The native disulfide bonds can be re-formed from the fully reduced and denatured state by oxidative refolding, resulting in a domain that is spectroscopically indistinguishable from the original refolded residual pro-part. Both disulfides are solvent-exposed and can be reduced in the absence of denaturant. The reduced form retains most or all of the native tertiary structure and is only approximately 2 kcal.mol(-1) less stable than the oxidized form. It folds fast relative to the rate of biosynthesis, to the same conformation as the oxidized form. Folding and disulfide formation are sequential. These results indicate that the proenzyme folds sequentially in vivo and that the residual pro-part constitutes a rapidly and independently folding domain that stabilizes the mature enzyme. It thus fulfills the criteria required of an intramolecular chaperone. It may also be involved in stabilizing the tetrameric structure of the mature enzyme. Study holds ProTherm entries: 10236, 10237 Extra Details: additive : DTT(20 mM), tertiary interactions; transient intermediates; disulfide bonds;,intramolecular chaperone

Submission Details

ID: P9Msuq8n

Submitter: Connie Wang

Submission Date: April 24, 2018, 8:40 p.m.

Version: 1

Publication Details
Cigić B;Dahl SW;Pain RH,Biochemistry (2000) The residual pro-part of cathepsin C fulfills the criteria required for an intramolecular chaperone in folding and stabilizing the human proenzyme. PMID:11015218
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
4OEL 2015-03-25 1.4 Crystal structure of Cathepsin C in complex with dipeptide substrates
4OEM 2015-03-25 1.52 Crystal structure of Cathepsin C in complex with dipeptide substrates
3PDF 2011-10-26 1.85 Discovery of Novel Cyanamide-Based Inhibitors of Cathepsin C
6IC6 2019-04-24 1.9 Human cathepsin-C in complex with cyclopropyl peptidyl nitrile inhibitor 1
6IC5 2019-04-24 2.0 Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 2
6IC7 2019-04-24 2.0 Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 3
2DJF 2006-11-14 2.0 Crystal Structure of human dipeptidyl peptidase I (Cathepsin C) in complex with the inhibitor Gly-Phe-CHN2
2DJG 2006-11-14 2.05 Re-determination of the native structure of human dipeptidyl peptidase I (cathepsin C)
1K3B 2002-04-02 2.15 Crystal Structure of Human Dipeptidyl Peptidase I (Cathepsin C): Exclusion Domain Added to an Endopeptidase Framework Creates the Machine for Activation of Granular Serine Proteases
4CDF 2014-03-19 2.2 Human DPP1 in complex with (2S,4S)-N-((1S)-1-cyano-2-(4-(4- cyanophenyl)phenyl)ethyl)-4-hydroxy-piperidine-2-carboxamide
4CDD 2014-03-19 2.35 Human DPP1 in complex with (2S)-N-((1S)-1-cyano-2-(4-(4-cyanophenyl) phenyl)ethyl)piperidine-2-carboxamide
4CDC 2014-03-19 2.4 Human DPP1 in complex with (2S)-2-amino-N-((1S)-1-cyano-2-(4- phenylphenyl)ethyl)butanamide
4CDE 2014-03-19 2.4 Human DPP1 in complex with 4-amino-N-((1S)-1-cyano-2-(4-(4- cyanophenyl)phenyl)ethyl)tetrahydropyran-4-carboxamide

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
278.3 A,B,C Human Dipeptidyl Peptidase I (Cathepsin C) Q3ZCJ8 CATC_BOVIN
288.6 A,B,C Human Dipeptidyl Peptidase I (Cathepsin C) Q60HG6 CATC_MACFA
296.59999999999997 A,B,C Human Dipeptidyl Peptidase I (Cathepsin C) Q5RB02 CATC_PONAB
300.0 A,B,C Human Dipeptidyl Peptidase I (Cathepsin C) P53634 CATC_HUMAN
95.7 C Human Dipeptidyl Peptidase I (Cathepsin C) O97578 CATC_CANLF