How cells prevent heavy metal accumulation

Many transition metals such as copper, zinc, and cobalt play pivotal roles in biochemical processes and are thus critical for cellular metabolic activity and survival. In contrast, cadmium, mercury and lead are toxic and impair certain biochemical pathways and cells have evolved mechanisms to remove these metals from their intracellular environment.

Heavy metals are translocated outside of the cell by transmembrane P1B-type ATPases, which utilise the energy of ATP. However, the detailed mechanism by which these molecular machines perform their function is incompletely understood.

Scientists on the EU-funded P1BPUMPS (Structural and functional characterization of molecular nanomachines: principles of transition metal selectivity and transport in heavy metal P1B-type ATPases) project employed a multidisciplinary structural and biochemical approach to obtain molecular information on the structure and function of these transporters. They successfully expressed and purified recombinant proteins from different archaea and bacteria species for structural, biochemical, biophysical and functional characterisation. They determined the metal selectivity of a number of P1B-type ATPases and investigated their uniporter or antiporter activity.

The consortium used different spectroscopic techniques to identify the metal binding sites and determine the geometry of metal binding as well as the chemistry underlying metal translocation. In addition, scientists reconstituted the purified proteins in artificial lipid bilayers and used fluorescent probes to monitor metal transport in real time.

Collectively, the activities of the P1BPUMPS study unveiled the molecular principles underlying metal transport across biological membranes. Importantly, the understanding of the structure and function of these P1B ATPase pumps will help towards the design of modulators of their activity.