Copper trafficking to the secretory pathway

Abstract

Copper (Cu) is indispensible for growth and development of human organisms. It is required for such fundamental and ubiquitous processes as respiration and protection against reactive oxygen species. Cu also enables catalytic activity of enzymes that critically contribute to the functional identity of many cells and tissues. Pigmentation, production of norepinephrine by the adrenal gland, the key steps in the formation of connective tissue, neuroendocrine signaling, wound healing – all these processes require Cu and depend on Cu entering the secretory pathway. To reach the Cu-dependent enzymes in a lumen of the trans-Golgi network and various vesicular compartments, Cu undertakes a complex journey crossing the extracellular and intracellular membranes and staying firmly on course while traveling in a cytosol. The proteins that assist Cu in this journey by mediating its entry, distribution, and export, have been identified. The accumulating data also indicate that the current model of cellular Cu homeostasis is still a “skeleton” that has to be fleshed out with many new details. This review summarizes recent data on the mechanisms responsible for Cu transfer to the secretory pathway. The emerging new concepts and gaps in our knowledge are discussed.

The Glutathione/Metallothionein System Challenges the Design of Efficient O2‐Activating Copper Complexes

“…2 % 20 min 0.10 AE 0.06 À0.14 [33] Cu II -gtsm % 50 min 0.49 AE 0.10 À0.24 [29] Cu II -Dp44mT % 4min 0.92 AE 0.11 À0.21 [34] Cu II -(5,5'-DmBipy) 2 < 30 sec 10.1 AE 1.0 0.12 [35] Cu II -(Phen) 2 < 30 sec 12.4 AE 1.7 0.17 [35] Cu I -(BCS) 2 < 30 sec 0.07 AE 0.01 0.62 [36] Angewandte Chemie Forschungsartikel Based on the rates of AscH À oxidation by O 2 ,catalyzed by the copper complexes,t hese were ranked in three arbitrary groups for ease of discussion ( Figure 2), namely,h igh efficiency copper complexes (group 1: r obs > 9 mm min À1 ), low efficiency copper complexes (group 2: 0.48 mm min À1 < r obs < 1.02 mm min À1 ), and inefficient copper complexes (group 3: r obs < 0.20 mm min À1 ). Group 1includes Cu II -(Phen) 2 and Cu II -(5,5'-DmBipy) 2 ,w hich are very active in catalyzing AscH À oxidation, with values of oxidation rates of about the same order of copper in buffer (Phen = 1,10-phenantroline;5 ,5 ' -DmBipy = 5,5'-dimethyl-2,2'-dipyridyl). Cu II -Dp44mT and Cu II -gtsm are part of group 2, being able to oxidize AscH À but slowly (Dp44mT = di-2-pyridylketone-4,4,-dimethyl-3thiosemicarbazone;g tsm = glyoxal-bis(N 4 -methyl-3-thiosemicarbazone).…”

“…Ther edox activity of the copper complexes generally correlate with their respective redox potentials,a lthough these potentials were mostly obtained in organic solvents and in the absence of substrates.However,itisnot known if these copper complexes react by an inner-o ro uter-sphere mechanism, so no causal and quantitative relationship between AscH À oxidation and redox potential can be made.C u II -(Phen) 2 and Cu II -(5,5'-DmBipy) 2 are thermodynamically more favourable for Cu II reduction to Cu I (namely, % 0.2 V vs.N HE) in the presence of AscH À (E8 8 AscH À /AscHC À = 0.28 V), compared to those of Cu II -gtsm and Cu II -Dp44mT (namely,approximately À0.2 Vvs. NHE).…”

“…To better control the timing of the different additions,t he kinetics were slowed down by lowering the concentrations of Cu II and thus of the in-situ-formed copper complex (namely,1mm Cu II ). These measurements confirmed what was previously observed with the preformed copper complexes.T he only differences were that group 1c omplexes (namely,C u II -(Phen) 2 and Cu II -(5,5'-DmBipy) 2 )oxidized AscH À much faster than copper in buffer and that cyclam needed time to arrest AscH À oxidation, in line with the slow kinetics of complexation of Cu II . [26] Next, the stability of the copper complexes in the presence of cytosolic-and/or nuclear-relevant concentrations of GSH and Zn-MT (namely,3m m and 2.5 mm, respectively) was investigated (corresponding to 4:1mol mol À1 CuL 1/2 :MT).…”

The Cu chaperone CopZ is required for Cu homeostasis in Rhodobacter capsulatus and influences cytochrome cbb3 oxidase assembly

“…CopZ-like Cu-chaperones have been identified as major determinants for Cu detoxification because they can bind Cu with femtomolar affinity (Xiao et al, 2011) and can transfer it to P 1B -type ATPases for extrusion. This has been shown for Atox1, which delivers Cu to ATP7B in the trans-Golgi network of human cells (Lutsenko, 2016) or for CopZ, which delivers Cu to CopA in the bacterial membrane (Odermatt and Solioz, 1995;Gonzalez-Guerrero and Arguello, 2008). In contrast to the CopA-like ATPases, the CcoI/FixI-like ATPases transport Cu primarily for cbb 3 -Cox assembly (Preisig et al, 1996;Koch et al, 1998a;Kulajta et al, 2006) and whether they also receive Cu from CopZ or any other Cu chaperone is unknown.…”

The dilemma to diagnose Wilson disease by genetic testing alone

“…25 Bacterial metabolites like the siderophore yersiniabactin, a polypeptide-polyketide produced by infectious Yersinia species and uropathogenic E coli 26 or methanobactin produced by Methylosinus trichosporium OB3b 27 may influence/modulate dietary copper absorption directly by binding copper. Copper transfer to the secretory pathway in hepatocytes is a sophisticated process orchestrated by both soluble and membrane proteins.…”