ATP7A transports cytosolic Cu2+ to phagosomal lumen

Stable Identifier
R-HSA-6803545
Type
Reaction [transition]
Species
Homo sapiens
Compartment
Synonyms
Copper export from cells by copper-transporting ATPase1
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Copper is an essential cofactor of key metabolic enzymes (Linder MC & Hazegh-Azam M 1996). Under normal conditions, the biosynthetic incorporation of copper into secreted and plasma membrane-bound proteins requires activity of the copper-transporting P1B-type ATPases (Cu-ATPases), ATP7A and ATP7B (Camakaris J et al. 1999; La Fontaine S & Mercer JF 2007; Lutsenko S et al. 2007). The Cu-ATPases also export excess copper from the cell and thus critically contribute to the homeostatic control of copper (Camakaris J et al. 1999; La Fontaine S & Mercer JF 2007). However, during bacterial infection phagocytic cells accumulate copper Cu(I) in cytoplasmic vesicles that partially fuse with the phagolysosome, attacking invading microbes with toxic levels of Cu (Festa RA & Thiele DJ 2012). The accumulation of Cu(I) in the phagosome may be dependent upon the trafficking of ATP7A to the membranes of these vesicles (Fu Y et al. 2014). Silencing of ATP7A expression in mouse RAW264.7 macrophages attenuated bacterial killing, suggesting a role for ATP7A-dependent copper transport in the bactericidal activity of macrophages (White C et al. 2009). Copper toxicity targets iron-sulfur containing proteins via iron displacement from solvent-exposed iron-sulfur clusters (Macomber L & Imlay JA 2009; Chillappagari S et al. 2010; Djoko KY & McEwan AG 2013). Copper resistance has been shown to be required for virulence in two animal models of mycobacterial infection (Wolschendorf F et al. 2011; Shi X et al. 2014).

Mutations in the gene encoding ATP7A results in a severe copper-deficiency known as Menkes disease (Kaler SG 2011).

Literature References
PubMed ID Title Journal Year
23028306 Copper at the front line of the host-pathogen battle

Festa, RA, Thiele, DJ

PLoS Pathog. 2012
26055706 The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens

Djoko, KY, Ong, CL, Walker, MJ, McEwan, AG

J. Biol. Chem. 2015
22389498 Copper homeostasis at the host-pathogen interface

Hodgkinson, V, Petris, MJ

J. Biol. Chem. 2012
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
copper transmembrane transporter activity, phosphorylative mechanism of ATP7A:PDZD11 [phagocytic vesicle membrane]
Physical Entity
Activity
Orthologous Events
Authored
Reviewed
Created