Abstract
Membrane proteins control the flow of ions across biological membranes by selective import or export and are of vital importance for all living cells. ATP7B is a human P-type ATPase that exports copper from the cytoplasm for excretion or incorporation into proteins, and mutations in ATP7B lead to the copper metabolism disorder Wilson's disease. ATP7B activity is regulated by an N-terminal heavy metal binding domain (HMBD), which is believed to display different dynamics and interaction patterns of its six metal binding domains (MBDs) in response to changes in copper concentration. Because the HMBD is highly dynamic, does not form a compact structure, and contain MBDs that move as rigid bodies with transient copper-dependent interactions, experimental characterization is highly challenging. Despite much effort it is still unknown how the HMBD is arranged around the core protein, and the mechanism of regulation by copper binding is poorly understood. To determine copper-dependent differences in the HMBD structural dynamics, and possible interactions with the core protein, we simulated a homology model of ATP7B in an E2 ion-free state in a membrane environment in the presence and absence of HMBD-bound copper. The results show that the HMBD interacts extensively with the core protein, with distinct differences between the apo and holo state. Specifically, the HMBD adopts more extended conformations in the holo state, with MBD2 and MBD3 showing the greatest differences. The observed results support a regulation mechanism where copper binding results in loss of MBD1-3 interactions as a first step of enzyme activation.
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