Metallochaperones regulate intracellular copper levels.
Copper (Cu) is an important enzyme co-factor that is also extremely toxic at high intracellular concentrations, making active efflux mechanisms essential for preventing Cu accumulation. Here, we have investigated the mechanistic role of metallochaperones in regulating Cu efflux. We have constructed a computational model of Cu trafficking and efflux based on systems analysis of the Cu stress response of Halobacterium salinarum. We have validated several model predictions via assays of transcriptional dynamics and intracellular Cu levels, discovering a completely novel function for metallochaperones. We demonstrate that in addition to trafficking Cu ions, metallochaperones also function as buffers to modulate the transcriptional responsiveness and efficacy of Cu efflux. This buffering function of metallochaperones ultimately sets the upper limit for intracellular Cu levels and provides a mechanistic explanation for previously observed Cu metallochaperone mutation phenotypes.
Institute for Systems Biology, Seattle, WA, USA.
W Lee
WL
Pang
Amardeep
A
Kaur
Alexander V
AV
Ratushny
Aleksandar
A
Cvetkovic
Sunil
S
Kumar
Min
M
Pan
Adam P
AP
Arkin
John D
JD
Aitchison
Michael W W
MW
Adams
Nitin S
NS
Baliga
D003300:Copper / Q000378:metabolism*; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics; D019617:Halobacterium salinarum / Q000378:metabolism / Q000502:physiology; D006706:Homeostasis; D017136:Ion Transport; D013058:Mass Spectrometry; D056511:Metallochaperones / Q000235:genetics / Q000502:physiology*; D008962:Models, Theoretical; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
D056511:Metallochaperones; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D003300:Copper