[Structure-functional organization of eukaryotic high-affinity copper importer CTR1 determines its ability to transport copper, silver and cisplatin].
It was shown recently, that high affinity Cu(I) importer eukaryotic protein CTR1 can also transport in vitro abiogenic Ag(I) ions and anticancer drug cisplatin. At present there is no rational explanation how CTR1 can transfer platinum group, which is different by coordination properties from highly similar Cu(I) and Ag(I). To understand this phenomenon we analyzed 25 sequences of chordate CTR1 proteins, and found out conserved patterns of organization of N-terminal extracellular part of CTR1 which correspond to initial metal binding. Extracellular copper-binding motifs were qualified by their coordination properties. It was shown that relative position of Met- and His-rich copper-binding motifs in CTR1 predisposes the extracellular CTR1 part to binding of copper, silver and cisplatin. Relation between tissue-specific expression of CTR1 gene, steady-state copper concentration, and silver and platinum accumulation in organs of mice in vivo was analyzed. Significant positive but incomplete correlation exists between these variables. Basing on structural and functional peculiarities of N-terminal part of CTR1 a hypothesis of coupled transport of copper and cisplatin has been suggested, which avoids the disagreement between CTR1-mediated cisplatin transport in vitro, and irreversible binding of platinum to Met-rich peptides.
A N
AN
Skvortsov
E A
EA
Zatulovskiĭ
L V
LV
Puchkova
D020816:Amino Acid Motifs; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D002945:Cisplatin / Q000493:pharmacokinetics*; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009928:Organ Specificity; D012834:Silver / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490077:Slc31a1 protein, mouse; D012834:Silver; D003300:Copper; D002945:Cisplatin