Neuropeptide Amidation in<i>Drosophila</i>: Separate Genes Encode the Two Enzymes Catalyzing Amidation

Kolhekar, Aparna S.; Roberts, Marie S.; Jiang, Ning; Johnson, R. C.; Mains, Richard E.; Eipper, Betty A.; Taghert, Paul H.

doi:10.1523/jneurosci.17-04-01363.1997

Cited by 115 publications

(119 citation statements)

References 47 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…Mutants of the prohormone convertase 2 Drosophila ortholog, referred to as amontillado, display partial embryonic lethality, are defective in larval growth, and arrest during the first to second instar larval molt (34). Null mutants of the Drosophila amidating enzyme peptidylglycine-hydroxylating monooxygenase die as late embryos; in those mutants with a strong hypomorphic allele that lacks detectable peptidylglycine-hydroxylating monooxygenase enzymatic activity or protein, ϳ50% hatch and initially display normal behavior and then die as young larvae attempting to molt (35,36).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Molecular Basis of the Drosophila Mutations in Carboxypeptidase D

Sidyelyeva

Baker

Fricker

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Carboxypeptidase D (CPD) functions in the processing of proteins and peptides in the secretory pathway. Drosophila CPD is encoded by the silver gene (svr), which is differentially spliced to produce long transmembrane protein forms with three metallocarboxypeptidase (CP)-like domains and short soluble forms with a single CP domain. Many svr mutants have been reported, but the precise molecular defects have not been previously determined. In the present study, three mutant lines were characterized. svr Metallocarboxypeptidases (CPs)3 perform many physiological functions, ranging from the digestion of food to the biosynthesis of neuropeptides (1-10). CPs are divided into three subfamilies based on amino acid analysis: the A/B subfamily (1-3, 9), the N/E subfamily (4 -8, 10), and a recently discovered subfamily that includes Nna1 and related proteins but has not yet been demonstrated to have CP activity (11). Within each subfamily, the members show 35-60% amino acid sequence identity, but between subfamilies, there is only 15-25% amino acid sequence conservation. The A/B subfamily is primarily involved in protein digestion, either in the digestive track or elsewhere in the body. In contrast, the N/E subfamily plays more of a biosynthetic role by selectively removing specific residues from peptide processing intermediates, and this step often affects the biological properties of the substrate. In humans and mice, there are eight members of this N/E family, of which five show enzymatic activity (CPE, CPN, CPM, CPZ, and CPD); the remaining members of this subfamily (CPX1, CPX2, and AEBP-1/ACLP) are not active toward standard substrates (4 -8, 10, 12-15). In contrast, Drosophila contains only two members of this subfamily, one that has high homology to CPM and another that is a CPD homolog (16).CPD is unique among CPs in that it contains multiple CP-like domains, a transmembrane domain, and a short cytosolic tail (5). Humans, rats, mice, duck, and Drosophila CPD all contain three CP-like domains, of which the first two are enzymatically active and the third is missing key catalytic residues but still appears to retain the basic CP-like structure (16 -27). The functional significance of the three CP-like domains in CPD is not clear. One proposal is that the distinct pH optima of the first two domains enable CPD to be active throughout the secretory pathway, which ranges from neutral to acidic pH values (17, 28). In both duck and Drosophila, the first domain is more active at neutral pH, whereas the second domain is optimally active at pH 5-6 (16, 17, 28). Protein containing both domains together showed a broader pH optimum (17, 28).There are several known mutations for CPD in Drosophila that are collectively known as the silver, or svr, mutants based on the silvery body color of the viable mutants (27,29). In addition to the body color, the viable svr mutants have been reported to show altered wing shape and mating behavior in light (30, 31), although these results have not been adequately described in the literature....

show abstract

Section: Discussionmentioning

confidence: 99%

Characterization of the Molecular Basis of the Drosophila Mutations in Carboxypeptidase D

Sidyelyeva

Baker

Fricker

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…It is more likely that defects in multiple Cu proteins rather than loss of one specific protein function are responsible for the early embryonic lethal phenotype of the Ctr1 Ϫ/Ϫ mice. Interestingly, insertional inactivation of the Drosophila PHM gene encoding a subunit of the Cu-dependent peptidylglycyl ␣-amidating enzyme is embryonically lethal (47), although the role of this enzyme in mammalian development has not been determined yet. Therefore, whether the embryonic lethal phenotype observed in Ctr1-deficient mice is because of the defective activity of a protein that is critical for early embryo development or a cumulative effect of an overall reduction in the activities of many Cu-dependent proteins remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development

Lee

Prohaska

Thiele

2001

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

399

319

View full text Add to dashboard Cite

The trace metal copper (Cu) plays an essential role in biology as a cofactor for many enzymes that include Cu, Zn superoxide dismutase, cytochrome oxidase, ceruloplasmin, lysyl oxidase, and dopamine ␤-hydroxylase. Consequently, Cu transport at the cell surface and the delivery of Cu to intracellular compartments are critical events for a wide variety of biological processes. The components that orchestrate intracellular Cu trafficking and their roles in Cu homeostasis have been elucidated by the studies of model microorganisms and by the characterizations of molecular basis of Cu-related genetic diseases, including Menkes disease and Wilson disease. However, little is known about the mechanisms for Cu uptake at the plasma membrane and the consequences of defects in this process in mammals. Here, we show that the mouse Ctr1 gene encodes a component of the Cu transport machinery and that mice heterozygous for Ctr1 exhibit tissue-specific defects in copper accumulation and in the activities of copper-dependent enzymes. Mice completely deficient for Ctr1 exhibit profound growth and developmental defects and die in utero in mid-gestation. These results demonstrate a crucial role for Cu acquisition through the Ctr1 transporter for mammalian Cu homeostasis and embryonic development.

show abstract

“…The presence of the consensus modification site (GRKR; Fig. 1A,C) suggests that CCAP is likely amidated at the C terminus in this fly (see Kolhekar et al, 1997) as it is in other arthropods. The other 3 putative peptides are called here CCAP-associated peptides (CCAP-AP) I, II and III.…”

Section: Drosophila 54 Cnaftgcgrkrtypsyppfslfkrneveekpynneylseglsdlidmentioning

confidence: 90%

Targeted ablation of CCAP neuropeptide-containing neurons ofDrosophilacauses specific defects in execution and circadian timing of ecdysis behavior

et al. 2003

View full text Add to dashboard Cite

Insect growth and metamorphosis is punctuated by molts, during which a new cuticle is produced. Every molt culminates in ecdysis, the shedding of the remains of the old cuticle. Both the timing of ecdysis relative to the molt and the actual execution of this vital insect behavior are under peptidergic neuronal control. Based on studies in the moth, Manduca sexta, it has been postulated that the neuropeptide Crustacean cardioactive peptide (CCAP)plays a key role in the initiation of the ecdysis motor program. We have used Drosophila bearing targeted ablations of CCAP neurons (CCAP KO animals) to investigate the role of CCAP in the execution and circadian regulation of ecdysis. CCAP KO animals showed specific defects at ecdysis, yet the severity and nature of the defects varied at different developmental stages. The majority of CCAP KO animals died at the pupal stage from the failure of pupal ecdysis, whereas larval ecdysis and adult eclosion behaviors showed only subtle defects. Interestingly, the most severe failure seen at eclosion appeared to be in a function required for abdominal inflation, which could be cardioactive in nature. Although CCAP KO populations exhibited circadian eclosion rhythms, the daily distribution of eclosion events (i.e.,gating) was abnormal. Effects on the execution of ecdysis and its circadian regulation indicate that CCAP is a key regulator of the behavior. Nevertheless, an unexpected finding of this work is that the primary functions of CCAP as well as its importance in the control of ecdysis behaviors may change during the postembryonic development of Drosophila.

show abstract

Neuropeptide Amidation inDrosophila: Separate Genes Encode the Two Enzymes Catalyzing Amidation

Cited by 115 publications

References 47 publications

Characterization of the Molecular Basis of the Drosophila Mutations in Carboxypeptidase D

Characterization of the Molecular Basis of the Drosophila Mutations in Carboxypeptidase D

Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development

Targeted ablation of CCAP neuropeptide-containing neurons ofDrosophilacauses specific defects in execution and circadian timing of ecdysis behavior

Contact Info

Product

Resources

About