title: 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 2.8 Å 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 disease-associated 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.
authors.affiliation: Department of Molecular Cardiology, The Cleveland Clinic, Cleveland, Ohio, 44195.
authors.forename: Joseph
authors.initials: J
authors.lastname: Amick
authors.forename: Simon E
authors.initials: SE
authors.lastname: Schlanger
authors.forename: Christine
authors.initials: C
authors.lastname: Wachnowsky
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Moseng
authors.forename: Corey C
authors.initials: CC
authors.lastname: Emerson
authors.forename: Michelle
authors.initials: M
authors.lastname: Dare
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Luo
authors.forename: Sujay S
authors.initials: SS
authors.lastname: Ithychanda
authors.forename: Jay C
authors.initials: JC
authors.lastname: Nix
authors.forename: J A
authors.initials: JA
authors.lastname: Cowan
authors.forename: Richard C
authors.initials: RC
authors.lastname: Page
authors.forename: Saurav
authors.initials: S
authors.lastname: Misra
mesh_terms: D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D011485:Protein Binding
chemical_list: D018840:HSP70 Heat-Shock Proteins; D009711:Nucleotides; C080352:mortalin
keywords: Heat-shock protein 70; chaperone inhibitor; mitochondria; nucleotide binding; p53; protein quality control