NOVEL MOLYBDENUM CENTERS
Proteins Containing Novel Molybdenum Heterometallic Clusters

The orange protein (ORP), first isolated from the sulfate-reducing organism Desulfovibrio gigas, is found in several anaerobic bacteria. It harbors a unique molybdenum/copper heterometallic cluster, [S₂Mo^VIS₂Cu^IS₂Mo^VIS₂]³⁻ (Mo/Cu), revealed by EXAFS. The metal cofactor is stabilized in the binding pocket through non-covalent interactions, but it does not involve any of the common metal-binding amino acid side chains, such as cysteine, histidine, and methionine side chains. Moreover, ORP can be heterologously expressed and isolated in an apo-form, which can be subsequently reconstituted in a protein-assisted mode using Cu^II and tetrathiomolybdate (TTM, MoS₄²⁻) salts, to yield a reconstituted protein that is identical to the native holo-ORP.
The biological function of ORP is still unknown; however, it is tempting to suggest that it may be related to its ability to chelate copper. Cells developed several copper sequestration and trafficking mechanisms to prevent the metal from reaching toxic levels, through which copper is scavenged and transferred by transient and specific protein−protein interactions, without dissociation of the ''free'' metal inside the cell. In this context, TTM (part of the ORP Mo/Cu cluster) presents itself as an ideal ''trap'' for copper. Due to its reactivity with copper, TTM plays an antagonist role toward many copper-containing and copper-transferring proteins. TTM reactivity has also been explored for management of Wilson’s disease and other copper-dependent diseases, where the dietary supplementation of animal models with TTM allowed the observation of the formation of hepatic Mo/Cu clusters.Yet, to our knowledge, in spite of this well-known chemistry, the Mo/Cu complex is unique to ORP, and its identification in the D. gigas ORP in 20001 was surprising.
In this project, we aim to understand the mechanism of the in vivo formation of the ORP Mo/Cu cluster, as well as, its physiological role.

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