Handling Copper: A Paradigm for the Mechanisms of Metal Ion Homeostasis - Environmental Contamination: Health Risks and Ecological Restoration - page 281

perhaps.diffuse.through.the.cytoplasmic.(inner).membrane.(Beswick.et.al..
1976).. The. P-type. ATPase. transporter,. CopA,. is. located. in. the. inner. mem-
brane. and. functions. as. an. eflux. transporter,. detoxifying. the. cytoplasm.
from. copper. ions. (Rensing. et. al.. 2000).. Also. located. in. the. periplasm. is. a.
multi-copper. oxidase,. CueO,. that. has. similarly. been. demonstrated. to. aid.
in. copper. detoxiication. (Grass. and. Rensing. 2001).. The. expression. of. both.
the.CopA.and.CueO.proteins.are.regulated.by.a.cytoplasmic.copper.sensing.
protein.called.CueR.(Outten.et.al..2000,.Stoyanov.et.al..2001)..Another.eflux.
mechanism. for.copper.is.a.four-component.pump,. CusCFBA,.which.spans.
the.inner.membrane,.periplasm,.and.outer.membrane.(Munson.et.al..2000,.
Franke.et.al..2003)..Expression.of.this.pump,.in.part,.is.regulated.by.a.two-
component. signal. transduction. system. ( cusRS ),. that. involves. a. membrane.
bound.histidine.kinase.(CusS).and.a.cytoplasmic.response.regulator.(CusR).
(Munson. et. al.. 2000).. The. CusF. constituent. of. the. eflux. pump. is. a. copper.
chaperone.found.in.the.periplasm.that.can.trafic.Cu(I).to.the.CusCBA.chan-
nel.for.removal.through.the.outer.membrane.(Franke.et.al..2003).

Eukaryotic Model for Copper Regulation: Saccharomyces Cerevisae

With. the. presence. of. internal. organelles,. yeast. and. plants. have. a. similar.
copper.regulatory.system.which.includes.several.direct.homologs..Yeast.has.
a. copper. reductase. protein. complex,. Fre1/Fre2,. that. is. located. extracellu-
larly.to.reduce.Cu(II).to.Cu(I).for.uptake.(Figure.13.5).(Hassett.and.Kosman.
1995,.Georgatsou.et.al..1997)..A.total.of.three.Ctr.(Copper.transporter).pro-
teins. have. been. discovered. in. yeast.. Two. of. these. transporters,. Ctr1. and.
Ctr3,. are. located. in. the. plasma. membrane. and. data. suggest. that. they. are.

Fet3

Cu(ll)

Nucleus
Ace1

Ccc2

Cu(l)

Golgi Mac1

Fre1/2

ATX1

Crs5

Ctr1/3

Vacuole

CCS Cup1

Cu(l)

Ctr2

SOD1

Mitochondrion
Cco

Cox

FIGURE 13.5
Copper.traficking.proteins.and.pathways.in. Saccharomyces cerevisae .(solid.line.depicts.inter-
actions.demonstrated.through.experimental.data,. white.rectangles. symbolize.copper.reduc-
tases,. gray. rectangles. are. copper. transporters,. white. circles. represent. copper. targets,. and.
white.hexagons.are.metallothioneins).