Recent Advances in Metalloproteomics

Abstract

Interactions between proteins and metal ions and their complexes are important in many areas of the life sciences, including physiology, medicine, and toxicology. Despite the involvement of essential elements in all major processes necessary for sustaining life, metalloproteomes remain ill-defined. This is not only owing to the complexity of metalloproteomes, but also to the non-covalent character of the complexes that most essential metals form, which complicates analysis. Similar issues may also be encountered for some toxic metals. The review discusses recently developed approaches and current challenges for the study of interactions involving entire (sub-)proteomes with such labile metal ions. In the second part, transition metals from the fourth and fifth periods are examined, most of which are xenobiotic and also tend to form more stable and/or inert complexes. A large research area in this respect concerns metallodrug–protein interactions. Particular attention is paid to separation approaches, as these need to be adapted to the reactivity of the metal under consideration.

Toward a Mechanism-Driven Integrated Framework to Link Human Exposure to Multiple Toxic Metal(loid) Species with Environmental Diseases

“…Taken together, these results demonstrate that in vitro studies can provide useful insight into dynamic aspects of the toxicological chemistry of individual metal(loid) species in blood plasma and that ternary interactions between a toxic metal(loid) species, a plasma protein and a SMW metabolite (e.g., Cys, hCys and/or others) that unfold in the presence of 100 mM Cl − play an important role in the selective delivery of their 'cargo' to toxicological target organs. These findings are reminiscent of previously observed interactions between Cu 2+ , HSA and L-histidine [95], the kinetic aspects of which are still not completely understood [96], and conceptually related studies which have demonstrated that the binding of Zn 2+ to HSA is modified by the fatty acid myristate, with health-relevant ramifications in the organs downstream [97]. While it cannot be entirely excluded that Hg 2+ -induced conformational changes of HSA [98] play an important role in its translocation to target organs, the obtained results suggest that probing ternary interactions between other neurotoxic metal(loid) species, such as Mn 2+ , As III and Pb 2+ with their known plasma proteins and distinct SMW metabolites in the presence of 100 mM NaCl may be a fruitful strategy to uncover the biomolecular mechanisms that deliver their cargo to uptake mechanisms at the blood-brain-barrier (BBB), which is a prerequisite for their subsequent uptake into the brain to cause neurotoxicity.…”