Targeting Capacity and Conservation of PreP Homologues Localization in Mitochondria of Different Species

Alikhani, Nyosha; Berglund, Anders; Engmann, Tanja; Spånning, Erika; Vögtle, F.-Nora; Pavlov, Pavel F.; Meisinger, Chris; Langer, Thomas; Glaser, Elzbieta

doi:10.1016/j.jmb.2011.05.009

Cited by 40 publications

(32 citation statements)

References 44 publications

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“…51 and 52, respectively. Mitoplasts were obtained by osmotic swelling of the intact mitochondria (22). Chloroplasts were fractionated as described in ref.…”

Section: Methodsmentioning

confidence: 99%

“…Residues localized in both halves of the enzyme contribute to proteolysis, suggesting that the structure must close for the cleavage to occur (21). Later studies led to the identification of AtPreP orthologs in yeast and mammals, both localized in mitochondrial matrix (22,23). The human PreP also was shown to degrade amyloid-β peptides and has been associated with Alzheimer's disease (23).…”

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confidence: 99%

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Organellar oligopeptidase (OOP) provides a complementary pathway for targeting peptide degradation in mitochondria and chloroplasts

Kmiec¹,

Teixeira²,

Berntsson³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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104

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Both mitochondria and chloroplasts contain distinct proteolytic systems for precursor protein processing catalyzed by the mitochondrial and stromal processing peptidases and for the degradation of targeting peptides catalyzed by presequence protease. Here, we have identified and characterized a component of the organellar proteolytic systems in Arabidopsis thaliana, the organellar oligopeptidase, OOP (At5g65620). OOP belongs to the M3A family of peptidedegrading metalloproteases. Using two independent in vivo methods, we show that the protease is dually localized to mitochondria and chloroplasts. Furthermore, we localized the OPP homolog At5g10540 to the cytosol. Analysis of peptide degradation by OOP revealed substrate size restriction from 8 to 23 aa residues. Short mitochondrial targeting peptides (presequence of the ribosomal protein L29 and presequence of 1-aminocyclopropane-1-carboxylic acid deaminase 1) and N-and C-terminal fragments derived from the presequence of the ATPase beta subunit ranging in size from 11 to 20 aa could be degraded. MS analysis showed that OOP does not exhibit a strict cleavage pattern but shows a weak preference for hydrophobic residues (F/L) at the P1 position. The crystal structures of OOP, at 1.8-1.9 Å, exhibit an ellipsoidal shape consisting of two major domains enclosing the catalytic cavity of 3,000 Å 3 . The structural and biochemical data suggest that the protein undergoes conformational changes to allow peptide binding and proteolysis. Our results demonstrate the complementary role of OOP in targeting-peptide degradation in mitochondria and chloroplasts.

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“…51 and 52, respectively. Mitoplasts were obtained by osmotic swelling of the intact mitochondria (22). Chloroplasts were fractionated as described in ref.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Organellar oligopeptidase (OOP) provides a complementary pathway for targeting peptide degradation in mitochondria and chloroplasts

Kmiec¹,

Teixeira²,

Berntsson³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

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show abstract

“…One of the peptidases directly involved in the peptide degradations is Cym1/PreP (111)(112)(113). The peptides generated through proteolysis can also be exported outside mitochondria with the help of peptide exporter of the inner mitochondrial membrane.…”

Section: Degradation Of Mitochondrial Proteinsmentioning

confidence: 99%

Mitochondrial protein homeostasis

2013

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Mitochondria use 800-1,500 proteins to perform their biological functions in the eukaryotic cells. Distinct transport and sorting mechanisms are responsible for the delivery of proteins to the correct location within mitochondria. Mitochondrial proteins undergo processing events and form functional assemblies.Finally, non-functional proteins are cleared to maintain healthy mitochondria. We provide an overview of the processes collectively contributing to the maintenance of mitochondrial protein homeostasis, which is critical for cell physiology and survival.

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“…HPreP primarily localizes to the mitochondrial matrix, where it cuts an array of peptides into recyclable fragments (Alikhani et al, 2011a; Chow et al, 2009; Falkevall et al, 2006). Its substrates include N-terminal mitochondrial targeting peptides or presequences, the clearance of which is vital to proteostasis, as these peptides can insert into mitochondrial membranes, disrupting their electrical potential and uncoupling respiration (Koppen and Langer, 2007; Mossmann et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis of Substrate Recognition and Degradation by Human Presequence Protease

et al. 2014

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Summary Human Presequence Protease (hPreP) is an M16 metalloprotease localized in mitochondria. There, hPreP facilitates proteostasis by utilizing a ∼13,300Å3 catalytic chamber to degrade a diverse array of potentially toxic peptides, including mitochondrial presequences and amyloid-β (Aβ), the latter of which contributes to Alzheimer's disease pathogenesis. Here we report crystal structures for hPreP alone and in complex with Aβ, which show that hPreP uses size-exclusion and charge complementation for substrate recognition. These structures also reveal hPreP-specific features that permit a diverse array of peptides, with distinct distributions of charged and hydrophobic residues, to be specifically captured, cleaved, and their amyloidogenic features destroyed. SAXS analysis demonstrates that hPreP in solution exists in dynamic equilibrium between closed and open states, with the former being preferred. Furthermore, Aβ binding induces the closed state and hPreP dimerization. Together, these data reveal the molecular basis for flexible yet specific substrate recognition and degradation by hPreP.

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Targeting Capacity and Conservation of PreP Homologues Localization in Mitochondria of Different Species

Cited by 40 publications

References 44 publications

Organellar oligopeptidase (OOP) provides a complementary pathway for targeting peptide degradation in mitochondria and chloroplasts

Organellar oligopeptidase (OOP) provides a complementary pathway for targeting peptide degradation in mitochondria and chloroplasts

Mitochondrial protein homeostasis

Molecular Basis of Substrate Recognition and Degradation by Human Presequence Protease

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