Crystal structure of the nucleotide‐binding domain of mortalin, the mitochondrial Hsp70 chaperone

Joseph Amick; Simon E. Schlanger; Christine Wachnowsky; Mitchell A. Moseng; Corey C. Emerson; Michelle Dare; Wen‐I Luo; Sujay S. Ithychanda; Jay C. Nix; J. A. Cowan; Richard C. Page; Saurav Misra

doi:10.1002/pro.2466

journal article Apr 17, 2014

Crystal structure of the nucleotide‐binding domain of mortalin, the mitochondrial Hsp70 chaperone

Joseph Amick Simon E. Schlanger Christine Wachnowsky Mitchell A. Moseng Corey C. Emerson Michelle Dare Wen‐I Luo Sujay S. Ithychanda Jay C. Nix J. A. Cowan Richard C. Page

Saurav Misra

Protein Science Vol. 23 No. 6 pp. 833-842 · Wiley

View at Publisher Save 10.1002/pro.2466

Abstract

AbstractMortalin, 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.

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Details

Published: Apr 17, 2014
Vol/Issue: 23(6)
Pages: 833-842
License: View

Authors

J

Joseph Amick

Department of Molecular Cardiology The Cleveland Clinic Cleveland Ohio 44195

S

Simon E. Schlanger

Department of Molecular Cardiology The Cleveland Clinic Cleveland Ohio 44195

C

Christine Wachnowsky

Department of Chemistry The Ohio State University Columbus Ohio 43210

M

Mitchell A. Moseng

Department of Chemistry and Biochemistry Miami University Oxford Ohio 45056

C

Corey C. Emerson

Department of Chemistry and Biochemistry Miami University Oxford Ohio 45056

M

Michelle Dare

Department of Molecular Cardiology The Cleveland Clinic Cleveland Ohio 44195

W

Wen‐I Luo

Department of Chemistry The Ohio State University Columbus Ohio 43210

S

Sujay S. Ithychanda

Department of Molecular Cardiology The Cleveland Clinic Cleveland Ohio 44195

J

Jay C. Nix

Molecular Biology Consortium, Advanced Light Source Lawrence Berkeley National Laboratory Berkeley California 94720

J

J. A. Cowan

Department of Chemistry The Ohio State University Columbus Ohio 43210

R

Richard C. Page

Department of Chemistry and Biochemistry Miami University Oxford Ohio 45056

S

Saurav Misra

Department of Molecular Cardiology The Cleveland Clinic Cleveland Ohio 44195

Funding

U.S. National Institutes of Health (S.M.) Award: R01-GM080271

National Institutes of Health (R.C.P.) Award: T32-HL007914

U.S. Department of Energy, Office of Basic Energy Sciences (The Advanced Light Source) Award: DE-AC03-76SF00098

Cite This Article

Joseph Amick, Simon E. Schlanger, Christine Wachnowsky, et al. (2014). Crystal structure of the nucleotide‐binding domain of mortalin, the mitochondrial Hsp70 chaperone. Protein Science, 23(6), 833-842. https://doi.org/10.1002/pro.2466

Crystal structure of the nucleotide‐binding domain of mortalin, the mitochondrial Hsp70 chaperone

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