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Research Grant
Project Number1R35GM136239-01Funding AgencyNational Institutes of HealthEffective Date2020-05-01Expiration Date2021-04-30Funding Amount$299,673
PROJECT SUMMARY Copper is an essential trace element utilized by eukaryotic cells as an enzymatic redox cofactor. At high concentrations the metal is toxic, and complex homeostatic mechanisms have developed to ensure that it is maintained at the correct physiological level. Prokaryotes such as gram negative pathogens have a diminished requirement for the metal, and show sensitivity to copper at levels well tolerated by mammalian cells. For this reason, macrophages utilize pathogenic copper to…
Research Grant
Project Number5R01GM123725-04Funding AgencyNational Institutes of HealthEffective Date2020-03-01Expiration Date2021-02-28Funding Amount$361,457
Dysregulation of copper homeostasis has multiple consequences for human health. Mammalian cells use copper pumps to maintain homeostasis, metalate copper-dependent enzymes, and transfer copper from one organelle/cell/tissue to another. Of equal significance is the study of bacterial transporters and their role as virulence factors in pathogens. An important class of efflux pump, present in a number of gram-negative pathogenic organisms is the RND- type heavy metal exporter exemplified by the …
Research Grant
Project Number5R01GM123725-03Funding AgencyNational Institutes of HealthEffective Date2019-03-01Expiration Date2020-02-29Funding Amount$361,457
Dysregulation of copper homeostasis has multiple consequences for human health. Mammalian cells use copper pumps to maintain homeostasis, metalate copper-dependent enzymes, and transfer copper from one organelle/cell/tissue to another. Of equal significance is the study of bacterial transporters and their role as virulence factors in pathogens. An important class of efflux pump, present in a number of gram-negative pathogenic organisms is the RND- type heavy metal exporter exemplified by the …
Research Grant
Project Number5R01GM115214-04Funding AgencyNational Institutes of HealthEffective Date2019-02-01Expiration Date2020-01-31Funding Amount$334,272
? DESCRIPTION (provided by applicant): Copper monooxygenases are essential to human health. They catalyze the biosynthesis of neuropeptide hormones and catecholamine neurotransmitters, and thus have special significance with respect to the health of neuroendocrine pathways. Their lack of activity in patients with Menkes disease (caused by mutation of the ATP7A copper pump) leads to severe neurological dysfunction, while peptidylglycine monooxygenase is elevated in certain cancers where it sti…
Research Grant
Project Number5R01GM123725-02Funding AgencyNational Institutes of HealthEffective Date2018-03-01Expiration Date2019-02-28Funding Amount$361,457
Dysregulation of copper homeostasis has multiple consequences for human health. Mammalian cells use copper pumps to maintain homeostasis, metalate copper-dependent enzymes, and transfer copper from one organelle/cell/tissue to another. Of equal significance is the study of bacterial transporters and their role as virulence factors in pathogens. An important class of efflux pump, present in a number of gram-negative pathogenic organisms is the RND- type heavy metal exporter exemplified by the …
Research Grant
Project Number5R01GM115214-03Funding AgencyNational Institutes of HealthEffective Date2018-02-01Expiration Date2019-01-31Funding Amount$334,272
? DESCRIPTION (provided by applicant): Copper monooxygenases are essential to human health. They catalyze the biosynthesis of neuropeptide hormones and catecholamine neurotransmitters, and thus have special significance with respect to the health of neuroendocrine pathways. Their lack of activity in patients with Menkes disease (caused by mutation of the ATP7A copper pump) leads to severe neurological dysfunction, while peptidylglycine monooxygenase is elevated in certain cancers where it sti…
Research Grant
Project Number3R01GM115214-03S1Funding AgencyNational Institutes of HealthEffective Date2018-02-01Expiration Date2019-01-31Funding Amount$131,900
Copper monooxygenases are essential to human health. They catalyze the biosynthesis of neuropeptide hormones and catecholamine neurotransmitters, and thus have special significance with respect to the health of neuroendocrine pathways. Their lack of activity in patients with Menkes disease (caused by mutation of the ATP7A copper pump) leads to severe neurological dysfunction, while peptidylglycine monooxygenase is elevated in certain cancers where it stimulates tumor proliferation via over pr…
Publication
ID30271955Published Date2018-01-01JournalCommunications biology, 2018-01-01, Volume 1
The structures of metalloproteins that use redox-active metals for catalysis are usually exquisitely folded in a way that they are prearranged to accept their metal cofactors. Peptidylglycine α-hydroxylating monooxygenase (PHM) is a dicopper enzyme that catalyzes hydroxylation of the α-carbon of glycine-extended peptides for the formation of des-glycine amidated peptides. Here, we present the structures of apo-PHM and of mutants of one of the copper sites (H107A, H108A, and H172A) determined …
Publication
ID30456313Published Date2018-01-01JournalCommunications biology, 2018-01-01, Volume 1
CusCBAF represents an important class of bacterial efflux pump exhibiting selectivity towards Cu(I) and Ag(I). The complex is comprised of three proteins: the CusA transmembrane pump, the CusB soluble adaptor protein, and the CusC outer-membrane pore, and additionally requires the periplasmic metallochaperone CusF. Here we used spectroscopic and kinetic tools to probe the mechanism of copper transfer between CusF and CusB using selenomethionine labeling of the metal-binding Met residues coupl…
Publication
ID28533431Published Date2017-07-21JournalThe Journal of biological chemistry, 2017-07-21, Volume 292
Metallochaperones are a diverse family of trafficking molecules that provide metal ions to protein targets for use as cofactors. The copper chaperone for superoxide dismutase (Ccs1) activates immature copper-zinc superoxide dismutase (Sod1) by delivering copper and facilitating the oxidation of the Sod1 intramolecular disulfide bond. Here, we present structural, spectroscopic, and cell-based data supporting a novel copper-induced mechanism for Sod1 activation. Ccs1 binding exposes an electrop…
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Research Grants: 86
Publications: 15

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