The Catalytic and Protein-Protein Interaction Domains Are Required for APM1 Function

Hosein, Fazeeda N.; Bandyopadhyay, Anindita; Peer, Wendy Ann; Murphy, Angus S.

doi:10.1104/pp.109.148742

Cited by 9 publications

(29 citation statements)

References 65 publications

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“…Although we cannot fully exclude that the unsuccessful complementation of amp1 by HsGCPII was due to incorrect processing or subcellular targeting of the human protein in a plant cell environment, this does not seem to be a general issue (Hosein et al, 2010). Functional divergence between AMP1 and HsGCPII is not too surprising:…”

Section: Discussionmentioning

confidence: 92%

The small molecule hyperphyllin enhances leaf formation rate and mimics shoot meristem integrity defects associated with AMP1 deficiency

et al. 2016

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) is a member of the M28 family of carboxypeptidases with a pivotal role in plant development and stress adaptation. Its most prominent mutant defect is a unique hypertrophic shoot phenotype combining a strongly increased organ formation rate with enhanced meristem size and the formation of ectopic meristem poles. However, so far the role of AMP1 in shoot development could not be assigned to a specific molecular pathway nor is its biochemical function resolved. In this work we evaluated the level of functional conservation between AMP1 and its human homolog HsGCPII, a tumor marker of medical interest. We show that HsGCPII cannot substitute AMP1 in planta and that an HsGCPII-specific inhibitor does not evoke amp1-specific phenotypes. We used a chemical genetic approach to identify the drug hyperphyllin (HP), which specifically mimics the shoot defects of amp1, including plastochron reduction and enlargement and multiplication of the shoot meristem. We assessed the structural requirements of HP activity and excluded that it is a cytokinin analog. HP-treated wild-type plants showed amp1-related tissue-specific changes of various marker genes and a significant transcriptomic overlap with the mutant. HP was ineffective in amp1 and elevated the protein levels of PHAVOLUTA, consistent with the postulated role of AMP1 in miRNA-controlled translation, further supporting an AMP1-related mode of action. Our work suggests that plant and animal members of the M28 family of proteases adopted unrelated functions. With HP we provide a tool to characterize the plant-specific functions of this important class of proteins.Arabidopsis ALTERED MERISTEM PROGRAM1 (AMP1, At3G54720, MEROPS ID: M28.007) belongs to the Zn 2+

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Section: Discussionmentioning

confidence: 92%

The small molecule hyperphyllin enhances leaf formation rate and mimics shoot meristem integrity defects associated with AMP1 deficiency

et al. 2016

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“…The demonstration of important roles for the protein–protein interaction domains in plant orthologues of PSA indicates that a more indirect mechanism may be important. That similar aminopeptidases may be activated by dimerization provides a possible means by which our catalytically inactive PSA could stimulate other potentially protective proteases [59]. However, further work is required to understand the indirect mechanism(s) by which PSA has beneficial effects in multiple models of Alzheimer's disease and other neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity

Kruppa

Ott

Chandraratna

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The accumulation of β-amyloid (Aβ) peptide in the brain is one of the pathological hallmarks of Alzheimer's disease and is thought to be of primary aetiological significance. In an unbiased genetic screen, we identified puromycin-sensitive aminopeptidase (PSA) as a potent suppressor of Aβ toxicity in a Drosophila model system. We established that coexpression of Drosophila PSA (dPSA) in the flies' brains improved their lifespan, protected against locomotor deficits, and reduced brain Aβ levels by clearing the Aβ plaque-like deposits. However, confocal microscopy and subcellular fractionation of amyloid-expressing 7PA2 cells demonstrated that PSA localizes to the cytoplasm. Therefore, PSA and Aβ are unlikely to be in the same cellular compartment; moreover, when we artificially placed them in the same compartment in flies, we could not detect a direct epistatic interaction. The consequent hypothesis that PSA's suppression of Aβ toxicity is indirect was supported by the finding that Aβ is not a proteolytic substrate for PSA in vitro. Furthermore, we showed that the enzymatic activity of PSA is not required for rescuing Aβ toxicity in neuronal SH-SY5Y cells. We investigated whether the stimulation of autophagy by PSA was responsible for these protective effects. However PSA's promotion of autophagosome fusion with lysosomes required proteolytic activity and so its effect on autophagy is not identical to its protection against Aβ toxicity.

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“…The order of activity against small peptide substrates or to amino acid 7-amino-4-trifluoromethyl-coumarin conjugates are Tyr ≫ Ala . Pro ≫ Trp ¼ Leu Hosein et al, 2010). APM1 forms a dimer, and it appears that the dimer is the active form in planta, although the monomer shows enzymatic activity at least equal to that of the dimer in vitro Hosein et al, 2010).…”

Section: Apm1mentioning

confidence: 99%

“…Pro ≫ Trp ¼ Leu Hosein et al, 2010). APM1 forms a dimer, and it appears that the dimer is the active form in planta, although the monomer shows enzymatic activity at least equal to that of the dimer in vitro Hosein et al, 2010). APM1 activity is sensitive to puromycin, bestatin, apstatin (substrate mimics) and PAQ-22/PIQ-22 , which binds at an allosteric site and is specific for PSA (Kakuta et al, 2003).…”

Section: Apm1mentioning

confidence: 99%

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The role of multifunctional M1 metallopeptidases in cell cycle progression

Peer¹

2011

Annals of Botany

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† Background Metallopeptidases of the M1 family are found in all phyla (except viruses) and are important in the cell cycle and normal growth and development. M1s often have spatiotemporal expression patterns which allow for strict regulation of activity. Mutations in the genes encoding M1s result in disease and are often lethal. This family of zinc metallopeptidases all share the catalytic region containing a signature amino acid exopeptidase (GXMXN) and a zinc binding (HEXXH[18X]E) motif. In addition, M1 aminopeptidases often also contain additional membrane association and/or protein interaction motifs. These protein interaction domains may function independently of M1 enzymatic activity and can contribute to multifunctionality of the proteins. † Scope A brief review of M1 metalloproteases in plants and animals and their roles in the cell cycle is presented. In animals, human puromycin-sensitive aminopeptidase (PSA) acts during mitosis and perhaps meiosis, while the insect homologue puromycin-sensitive aminopeptidase (PAM-1) is required for meiotic and mitotic exit; the remaining human M1 family members appear to play a direct or indirect role in mitosis/cell proliferation. In plants, meiotic prophase aminopeptidase 1 (MPA1) is essential for the first steps in meiosis, and aminopeptidase M1 (APM1) appears to be important in mitosis and cell division. † Conclusions M1 metalloprotease activity in the cell cycle is conserved across phyla. The activities of the multifunctional M1s, processing small peptides and peptide hormones and contributing to protein trafficking and signal transduction processes, either directly or indirectly impact on the cell cycle. Identification of peptide substrates and interacting protein partners is required to understand M1 function in fertility and normal growth and development in plants.

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The Catalytic and Protein-Protein Interaction Domains Are Required for APM1 Function

Cited by 9 publications

References 65 publications

The small molecule hyperphyllin enhances leaf formation rate and mimics shoot meristem integrity defects associated with AMP1 deficiency

The small molecule hyperphyllin enhances leaf formation rate and mimics shoot meristem integrity defects associated with AMP1 deficiency

Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity

The role of multifunctional M1 metallopeptidases in cell cycle progression

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