Folding Incompetence of Cathepsin L-Like Cysteine Proteases May Be Compensated by the Highly Conserved, Domain-Building N-Terminal Extension of the Proregion

Schilling, Klaus; Pietschmann, Sandra; Fehn, Marc; Wenz, Ingrid; Wiederanders, Bernd

doi:10.1515/bchm.2001.382.5.859

Cited by 9 publications

(10 citation statements)

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“…This fits very well with the phenomenon seen in some peptidases where N-terminal folded structures can provide a scaffold for further folding and thus facilitate the process in vivo (Frydman, 2001). In cathepsin L like cysteine proteases, a mini-domain in the propeptide represents this nucleation centre and is suggested to be the structural correlate of its foldase function (Schilling et al, 2001).…”

Section: Folding Assistancesupporting

confidence: 81%

“…The initial contact induces in both the propeptide and the enzyme a conformational shift resulting in k off values of the complexes resembling those of the cognate propeptide/enzyme pairs. This was observed with mutants destabilizing the mini domain between helices a1 and a2 in procathepsin S (Schilling et al, 2001) and also for the inhibition of cathepsin H by the cathepsin L propeptide (own unpublished result).…”

Section: Selectivity Of Inhibitionmentioning

confidence: 61%

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Structure-function relationships in class CA1 cysteine peptidase propeptides.

Wiederanders¹

2003

Acta Biochim Pol

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Regulation of proteolytic enzyme activity is an essential requirement for cells and tissues because proteolysis at a wrong time and location may be lethal. Proteases are synthesized as inactive or less active precursor molecules in order to prevent such inappropriate proteolysis. They are activated by limited intra- or intermolecular proteolysis cleaving off an inhibitory peptide. These regulatory proenzyme regions have attracted much attention during the last decade, since it became obvious that they harbour much more information than just triggering activation. In this review we summarize the structural background of three functions of clan CA1 cysteine peptidase (papain family) proparts, namely the selectivity of their inhibitory potency, the participation in correct intracellular targeting and assistance in folding of the mature enzyme. Today, we know more than 500 cysteine peptidases of this family from the plant and animal kingdoms, e.g. papain and the lysosomal cathepsins L and B. As it will be shown, the propeptide functions are determined by certain structural motifs conserved over millions of years of evolution.

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Section: Folding Assistancesupporting

confidence: 81%

Section: Selectivity Of Inhibitionmentioning

confidence: 61%

Structure-function relationships in class CA1 cysteine peptidase propeptides.

Wiederanders¹

2003

Acta Biochim Pol

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“…Conservation suggests functional and/or structural importance. The role of 10 conserved prosegment residues in procathepsin S has been probed by alanine scanning, both in vitro (Schilling et al 2001; Pietschmann et al 2002) and in vivo (Kreusch et al 2000). Pietschmann et al (2002) correlated the structural integrity of recombinant propeptide mutants, scaled by the red shift of the endogenous tryptophan fluorescence, with two basic functions, inhibition and folding, of the parental enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…Renaturation rates ( left ordinate, •) are from Pietschmann et al (2002). Inhibiton constants ( right ordinate, □) and red shift of the endogenous tryptophan fluorescence, standing for compactness of tertiary structure (abscissa), are from Schilling et al (2001).…”

Section: Discussionmentioning

confidence: 99%

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The crystal structure of a Cys25 → Ala mutant of human procathepsin S elucidates enzyme–prosequence interactions

et al. 2006

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The crystal structure of the active-site mutant Cys25 !Ala of glycosylated human procathepsin S is reported. It was determined by molecular replacement and refined to 2.1 Å resolution, with an R-factor of 0.198. The overall structure is very similar to other cathepsin L-like zymogens of the C1A clan. The peptidase unit comprises two globular domains, and a small third domain is formed by the N-terminal part of the prosequence. It is anchored to the prosegment binding loop of the enzyme. Prosegment residues beyond the prodomain dock to the substrate binding cleft in a nonproductive orientation. Structural comparison with published data for mature cathepsin S revealed that procathepsin S residues Phe146, Phe70, and Phe211 adopt different orientations. Being part of the S19 and S2 pockets, they may contribute to the selectivity of ligand binding. Regarding the prosequence, length, orientation and anchoring of helix a3p differ from related zymogens, thereby possibly contributing to the specificity of propeptide-enzyme interaction in the papain family. The discussion focuses on the functional importance of the most conserved residues in the prosequence for structural integrity, inhibition and folding assistance, considering scanning mutagenesis data published for procathepsin S and for its isolated propeptide.

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