title: Physical interaction and functional coupling between ACDP4 and the intracellular ion chaperone COX11, an implication of the role of ACDP4 in essential metal ion transport and homeostasis.
abstract: Divalent metal ions such as copper, manganese, and cobalt are essential for cell development, differentiation, function and survival. These essential metal ions are delivered into intracellular domains as cofactors for enzymes involved in neuropeptide and neurotransmitter synthesis, superoxide metabolism, and other biological functions in a target specific fashion. Altering the homeostasis of these essential metal ions is known to connect to a number of human diseases including Alzheimer disease, amyotrophic lateral sclerosis, and pain. It remains unclear how these essential metal ions are delivered to intracellular targets in mammalian cells. Here we report that rat spinal cord dorsal horn neurons express ACDP4, a member of Ancient Conserved Domain Protein family. By screening a pretransformed human fetal brain cDNA library in a yeast two-hybrid system, we have identified that ACDP4 specifically interacts with COX11, an intracellular metal ion chaperone. Ectopic expression of ACDP4 in HEK293 cells resulted in enhanced toxicity to metal ions including copper, manganese, and cobalt. The metal ion toxicity became more pronounced when ACDP4 and COX11 were co-expressed ectopically in HEK293 cells, suggesting a functional coupling between them. Our results indicate a role of ACDP4 in metal ion homeostasis and toxicity. This is the first report revealing a functional aspect of this ancient conserved domain protein family. We propose that ACDP is a family of transporter protein or chaperone proteins for delivering essential metal ions in different mammalian tissues. The expression of ACDP4 on spinal cord dorsal horn neurons may have implications in sensory neuron functions under physiological and pathological conditions.
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, GA 30912, USA. dguo@mcg.edu
authors.forename: Dehuang
authors.initials: D
authors.lastname: Guo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ling
authors.forename: Mong-Heng
authors.initials: MH
authors.lastname: Wang
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
authors.forename: Jianguo
authors.initials: J
authors.lastname: Gu
authors.forename: Cong-Yi
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins; D002460:Cell Line; D017124:Conserved Sequence; D000079922:Copper Transport Proteins; D003593:Cytoplasm / Q000502:physiology; D045222:Electron Transport Chain Complex Proteins; D003576:Electron Transport Complex IV / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D017136:Ion Transport / Q000502:physiology*; D008670:Metals / Q000378:metabolism*; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones / Q000502:physiology*; D020671:Posterior Horn Cells / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C484188:COX11 protein, human; D027682:Cation Transport Proteins; C530931:Cnnm4 protein, rat; D000079922:Copper Transport Proteins; D045222:Electron Transport Chain Complex Proteins; D008670:Metals; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D003576:Electron Transport Complex IV