The silver gene of Drosophila melanogaster encodes multiple carboxypeptidases similar to mammalian prohormone-processing enzymes.

Settle, Stephen H.; Green, M. M.; Burtis, Kenneth C.

doi:10.1073/pnas.92.21.9470

Cited by 49 publications

(56 citation statements)

References 36 publications

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“…If these need to be removed for the products to be biologically active, as is the case for most neuroendocrine peptides, CPD is a likely candidate for this activity based on its tissue distribution, intracellular distribution, and pH optimum. The involvement of CPD in important biological functions is supported by the fact that the mutations in the Silver gene, the Drosophila homologue of CPD, are embryonic lethal (21).…”

Section: Resultsmentioning

confidence: 94%

Localization of Metallocarboxypeptidase D in AtT-20 Cells

Varlamov

Eng

Novikova

et al. 1999

Journal of Biological Chemistry

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Carboxypeptidase D (CPD) is a recently discovered metallocarboxypeptidase that is predominantly located in the trans-Golgi network (TGN), and also cycles between the cell surface and the TGN. In the present study, the intracellular distribution of CPD was examined in AtT-20 cells, a mouse anterior pituitary-derived corticotroph. CPD-containing compartments were isolated using antibodies to the CPD cytosolic tail. The immunopurified vesicles contained TGN proteins (TGN38, furin, syntaxin 6) but not lysosomal or plasma membrane proteins. The CPD-containing vesicles also contained neuropeptide-processing enzymes and adrenocorticotropic hormone, a product of proopiomelanocortin proteolysis. Electron microscopic analysis revealed that CPD is present within the TGN and immature secretory granules but is virtually absent from mature granules, suggesting that CPD is actively removed from the regulated pathway during the process of granule maturation. A second major finding of the present study is that a soluble truncated form of CPD is secreted mainly via the constitutive pathway in AtT-20 cells, indicating that the lumenal domain does not contain signals for the sorting of CPD to mature secretory granules. Taken together, these data are consistent with the proposal that CPD participates in the processing of proteins within the TGN and immature secretory vesicles.

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Section: Resultsmentioning

confidence: 94%

Localization of Metallocarboxypeptidase D in AtT-20 Cells

Varlamov

Eng

Novikova

et al. 1999

Journal of Biological Chemistry

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“…The two domains of angiotensin-converting enzyme are differentially affected by chloride and have different k cat values for substrates (51). It is likely that both the first and second carboxypeptidase domains of CPD perform important functions, since these two domains are conserved in all species examined, including mammals, Drosophila, and Aplysia (38,(43)(44)(45)(46). In addition, the high degree of conservation of the third domain of CPD among human, rat, and duck implies an important function for this domain as well.…”

Section: Discussionmentioning

confidence: 99%

“…Human, rat, and duck CPD consists of three carboxypeptidase-like domains, a transmembrane domain, and then a short cytosolic tail (38,43,44), whereas the Drosophila CPD homolog contains two (45) and the Aplysia homolog contains four carboxypeptidase-like domains (46). Thus, the general feature of multiple carboxypeptidase-like domains is highly conserved.…”

mentioning

confidence: 97%

Characterization of the Enzymatic Properties of the First and Second Domains of Metallocarboxypeptidase D

Novikova

Eng

Lin

et al. 1999

Journal of Biological Chemistry

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Carboxypeptidase D (CPD) contains three domains with homology to other metallocarboxypeptidases. To further characterize the various domains, we constructed a series of point mutants with a critical active site Glu of duck CPD converted to Gln. The proteins were expressed in the baculovirus system, purified to homogeneity, and characterized. Point mutations within both the first and second domains eliminated enzyme activity, indicating that the third domain is inactive toward dansyl-Phe-Ala-Arg. CPD removed only the C-terminal Lys or Arg from peptides, with the first domain more efficient toward Arg and the second domain more efficient toward Lys. Peptides containing Pro in the penultimate position were poorly cleaved by either domain. Cleavage of a peptide with Ala in the penultimate position was most efficient, with the relative order Ala > Met > Ser, Phe > Tyr > Trp > Thr > Gln, Asp, Leu, Gly Ͼ Ͼ Ͼ Ͼ Pro for CPD with both domains active. There were only minor differences between the first and the second domains regarding the influence of the penultimate amino acid. The first domain was optimally active at pH 6.3-7.5, whereas the second domain was optimally active at pH 5.0 -6.5. Thus, the first and second carboxypeptidase domains have complementary enzyme activities. Furthermore, the finding that CPD with both domains active shows a broad activity to a wide range of substrates is consistent with a role for this enzyme in the processing of many proteins that transit the secretory pathway.

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“…Pu also colocalizes with the QTL on chromosome 2. The silver (svr) gene, which encodes proteins that are members of the carboxypeptidase family (Settle et al 1995), colocalizes with the QTL at the tip of the X chromosome. Mutations in svr affect pigmentation, wing shape, and catecholamine pools (Wright 1987).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Trait Loci Affecting the Difference in Pigmentation BetweenDrosophila yakubaandD. santomea

et al. 2005

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Using quantitative trait locus (QTL) mapping, we studied the genetic basis of the difference in pigmentation between two sister species of Drosophila: Drosophila yakuba, which, like other members of the D. melanogaster subgroup, shows heavy black pigmentation on the abdomen of males and females, and D. santomea, an endemic to the African island of São Tomé, which has virtually no pigmentation. Here we mapped four QTL with large effects on this interspecific difference in pigmentation: two on the X chromosome and one each on the second and third chromosomes. The same four QTL were detected in male hybrids in the backcrosses to both D. santomea and D. yakuba and in the female D. yakuba backcross hybrids. All four QTL exhibited strong epistatic interactions in male backcross hybrids, but only one pair of QTL interacted in females from the backcross to D. yabuka. All QTL from each species affected pigmentation in the same direction, consistent with adaptive evolution driven by directional natural selection. The regions delimited by the QTL included many positional candidate loci in the pigmentation pathway, including genes affecting catecholamine biosynthesis, melanization of the cuticle, and many additional pleiotropic effects.

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The silver gene of Drosophila melanogaster encodes multiple carboxypeptidases similar to mammalian prohormone-processing enzymes.

Cited by 49 publications

References 36 publications

Localization of Metallocarboxypeptidase D in AtT-20 Cells

Localization of Metallocarboxypeptidase D in AtT-20 Cells

Characterization of the Enzymatic Properties of the First and Second Domains of Metallocarboxypeptidase D

Quantitative Trait Loci Affecting the Difference in Pigmentation BetweenDrosophila yakubaandD. santomea

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