Evidences for zinc (II) and copper (II) ion interactions with Mycobacterium leprae HSP18: Effect on its structure and...

Mycobacterium leprae uptakes various bivalent metal ions via different transporters in host species. Uptake of Cu²⁺ and Zn²⁺ are essential for generation of superoxide dismutases and catalases, which provide defense against reactive oxygen species mediated death of this pathogen in macrophages. Furthermore, it has also been noticed that levels of different bivalent metal ions (Ca²⁺, Mg²⁺, Cu²⁺ and Zn²⁺) in blood serum are altered in leprotic patients. Mycobacterium leprae HSP18 is an immunodominant antigen which helps in growth and survival of Mycobacterium leprae in host species. A possible link can exist between HSP18 and aberration of bivalent metal ion homeostasis. Therefore, we investigated the interaction of these four bivalent metal ions with HSP18 and found that the protein only interacts with Zn²⁺ and Cu²⁺. Such association process is reversible and moderately high affinity in nature with unit binding stoichiometry. Theoretical studies revealed that the most probable site for Zn²⁺-binding lies in the N-terminal domain; While, the same for Cu²⁺-binding lies in the "α-crystallin domain" of HSP18. Binding of Zn²⁺/Cu²⁺ to HSP18 brings about subtle changes in the secondary and tertiary structure of HSP18 but are distinctly opposite in nature. While Zn²⁺ causes oligomeric association, Cu²⁺ leads to oligomeric dissociation of HSP18. Structural stability, surface hydrophobicity and chaperone activity of HSP18 are enhanced on Zn²⁺ binding, while all of them are reduced upon Cu²⁺ binding. Altogether, metal ions binding to HSP18 regulate its function which may have far reaching effect on the survival and pathogenicity of Mycobacterium leprae in host species.