Prosegment of tripeptidyl peptidase I is a potent, slow-binding inhibitor of its cognate enzyme.

The Journal of Biological Chemistry
Adam A GolabekElizabeth Kida

Abstract

Tripeptidyl peptidase I (TPP I) is the first mammalian representative of a family of pepstatin-insensitive serine-carboxyl proteases, or sedolisins. The enzyme acts in lysosomes, where it sequentially removes tripeptides from the unmodified N terminus of small, unstructured polypeptides. Naturally occurring mutations in TPP I underlie a neurodegenerative disorder of childhood, classic late infantile neuronal ceroid lipofuscinosis (CLN2). Generation of mature TPP I is associated with removal of a long prosegment of 176 amino acid residues from the zymogen. Here we investigated the inhibitory properties of TPP I prosegment expressed and isolated from Escherichia coli toward its cognate protease. We show that the TPP I prosegment is a potent, slow-binding inhibitor of its parent enzyme, with an overall inhibition constant in the low nanomolar range. We also demonstrate the protective effect of the prosegment on alkaline pH-induced inactivation of the enzyme. Interestingly, the inhibitory properties of TPP I prosegment with the introduced classic late infantile neuronal ceroid lipofuscinosis disease-associated mutation, G77R, significantly differed from those revealed by wild-type prosegment in both the mechanism of interaction and...Continue Reading

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Citations

Aug 4, 2010·Cellular and Molecular Life Sciences : CMLS·Amanda L Getty, David A Pearce
Feb 14, 2013·Biochimica Et Biophysica Acta·Katrin KollmannThomas Braulke
Oct 1, 2010·Biomolecular Concepts·Ilya V DemidyukSergey V Kostrov
Apr 16, 2020·Critical Reviews in Biochemistry and Molecular Biology·Lise BoonGhislain Opdenakker

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