Crystal structure of the nucleotide-Binding domain of mortalin, the mitochondrial Hsp70 chaperone

Abstract

Mortalin, a member of the Hsp70-Family of molecular chaperones, functions in a variety of processes including mitochondrial protein import and quality control, Fe-S cluster protein biogenesis, mitochondrial homeostasis, and regulation of p53. Mortalin is implicated in regulation of apoptosis, cell stress response, neurodegeneration, and cancer and is a target of the antitumor compound MKT-077. Like other Hsp70-Family members, Mortalin consists of a nucleotide-Binding domain (NBD) and a substrate-Binding domain. We determined the crystal structure of the NBD of human Mortalin at 2.8A resolution. Although the Mortalin nucleotide-Binding pocket is highly conserved relative to other Hsp70 family members, we find that its nucleotide affinity is weaker than that of Hsc70. A Parkinson's diseaseassociated mutation is located on the Mortalin-NBD surface and may contribute to Mortalin aggregation. We present structure-Based models for how the Mortalin-NBD may interact with the nucleotide exchange factor GrpEL1, with p53, and with MKT-077. Our structure may contribute to the understanding of disease-associated Mortalin mutations and to improved Mortalin-Targeting antitumor compounds. ©2014 The Protein Society.