Metal transport mechanism of the cation diffusion facilitator (CDF) protein family-a structural perspective on human CDF (ZnT)-related diseases

Divalent d-block metal cations (DDMCs) participate in many cellular functions; however, their accumulation in cells can be cytotoxic. The cation diffusion facilitator (CDF) family is a ubiquitous family of transmembrane DDMC exporters that ensures their homeostasis. Severe diseases, such as type II diabetes, Parkinson's and Alzheimer's disease, were linked to dysfunctional human CDF proteins, ZnT-1-10 (SLC30A1-10). Each member of the CDF family reduces the cytosolic concentration of a specific DDMC by transporting it from the cytoplasm to the extracellular environment or into intracellular compartments. This process is usually achieved by utilizing the proton motive force. In addition to their activity as DDMC transporters, CDFs also have other cellular functions such as the regulation of ion channels and enzymatic activity. The combination of structural and biophysical studies of different bacterial and eukaryotic CDF proteins led to significant progress in the understanding of the mutual interaction among CDFs and DDMCs, their involvement in ion binding and selectivity, conformational changes and the consequent transporting mechanisms. Here, we review these studies, provide our mechanistic interpretation of CDF proteins based on the current literature and relate the above to known human CDF-related diseases. Our analysis provides a common structure-function relationship to this important protein family and closes the gap between eukaryote and prokaryote CDFs.