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Mortalin Caught in Action: Structures of the Nucleotide Binding Domain in the Apo, ADP‐bound and AMP+PPi‐bound states

The heat shock protein 70, Hsp70, chaperone family plays key roles in cellular homeostasis and stress response. Hsp70s not only regulate the folding of nascent proteins, but also prevent aggregation, promote disaggregation, and refold misfolded proteins. The mitochondrial heat shock protein Mortalin functions in a variety of processes such as apoptosis, cellular stress response, mitochondrial protein import and quality control, Fe‐S cluster biogenesis, mitochondrial homeostasis, and regulation of p53, an important tumor suppressor. Mortalin is implicated in neurodegenerative diseases, and is known to play an anti‐apoptotic role in cancer cells. The Page laboratory has elucidated crystal structures of the nucleotide binding domain of human Mortalin in the apo, ADP‐bound, and AMP‐bound states at 2.8 Å, 2.78 Å, and 1.75 Å resolutions, respectively. The crystal structure of Mortalin‐NBD with the modified ADP homolog N6P‐ADP bound has also been determined at 1.49 Å. The overall structures and active site organizations are similar, with a few key differences in side chain positions. Our data identifies specific residues in the nucleotide binding pocket, which are not conserved in other Hsp70‐family members, that lead to lower nucleotide affinity and slower turnover relative to cytosolic Hsp70. Our structural data will also contribute to the understanding of disease‐associated Mortalin mutations and to improved Mortalin‐targeted compounds with the aim of influencing the function of Mortalin. Regulation of Mortalin has been proposed as a potential avenue for the treatment of cancer and neurodegenerative diseases.