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PresequenceProtease (PreP), a novel Peptidasome in Mitochondria and Chloroplasts : Localization, Function, Structure and Mechanism of Proteolysis

by Bhushan, Shashi

Abstract (Summary)
The information for mitochondrial and chloroplastic protein import and targeting generally resides in the N-terminal part of the protein, called a targeting peptide. The targeting peptide is cleaved off by the organellar processing peptidases after import of a precursor protein. Free targeting peptides generated inside the organelle after import are rapidly degraded by proteolysis as their accumulation can have toxic effects on the organelle. The aim of this thesis has been to investigate the newly identified targeting peptide degrading protease, the PresequenceProtease (PreP). We have shown that the two isoforms of Arabidopsis PreP (AtPreP1 and AtPreP1) are dually targeted and localized to both mitochondria and chloroplasts. Dual targeting of the AtPreP1 is due to an ambiguous targeting peptide with a domain organization for mitochondrial and chloroplastic targeting. Both the AtPreP1 and AtPreP2 are expressed in Arabidopsis in an organ specific manner and they have distinct but overlapping substrate specificity. The crystal structure of the recombinant AtPreP1 E80Q was solved at 2.1 Å resolution. The structure represents the first substrate bound, closed conformation of a protease from the pitrilysin family. The PreP polypeptide folds in a unique peptidasome structure, surrounding a huge cavity of more than 10 000 Å3 in which the active site resides. A novel mechanism for proteolysis is proposed involving hinge-bending motions in response to substrate binding. PreP in human mitochondria has a novel function: degradation of amyloid ?-peptide (A?). We show that under circumstances when A? is present in mitochondria of Alzheimer’s patients, PreP is the protease responsible for degradation of this toxic peptide.
Bibliographical Information:

Advisor:

School:Stockholms universitet

School Location:Sweden

Source Type:Doctoral Dissertation

Keywords:NATURAL SCIENCES; Chemistry; Biochemistry; Protein import; mitochondria; chloroplasts; PresequenceProtease; Alzheimer; biokemi; Biochemistry

ISBN:978-91-7155-435-2

Date of Publication:01/01/2007

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