Cu(II)-Binding N-Terminal Sequences of Human Proteins

Proteins anchor copper(II) ions mainly by imidazole from histidine residues located in different positions in the primary protein structures. However, the motifs with histidine in the first three N-terminal positions (His(1), His(2), and His(3)) show unique Cu(II)-binding properties, such as availability from the surface of the protein, high flexibility, and high Cu(II) exchangeability with other ligands. It makes such sequences beneficial for the fast exchange of Cu(II) between ligands. Furthermore, sequences with His(1) and His(2), thus, non-saturating the Cu(II) coordination sphere, are redox-active and may play a role in Cu(II) reduction to Cu(I). All human protein sequences deposited in UniProt Knowledgebase were browsed for those containing His(1), His(2), or His(3). Proteolytically modified sequences (with the removal of a propeptide or Met residue) were taken for the analysis. Finally, the sequences were sorted out according to the subcellular localization of the proteins to match the respective sequences with the probability of interaction with divalent copper.

Automated summary

Proteins mainly anchor copper(II) ions through imidazole clusters from histidine residues, with motifs containing histidine in the first three N-terminal positions showing unique Cu(II)-binding properties. These sequences are beneficial for fast Cu(II) exchange between ligands and may play a role in redox reactions.