Functional Significance of Point Mutations in Stress Chaperone Mortalin and Their Relevance to Parkinson Disease

Title
Functional Significance of Point Mutations in Stress Chaperone Mortalin and Their Relevance to Parkinson Disease
Authors
윤채옥
Keywords
RIBOSOMAL-PROTEIN L11; CELLULAR SENESCENCE; INDUCED APOPTOSIS; CANCER-CELLS; MOLECULAR CHAPERONES; HUMAN FIBROBLASTS; OXIDATIVE STRESS; HSP70 FAMILY; MOUSE MOT-1; IN-VITRO
Issue Date
2015-03
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v. 290, NO 13, Page. 8447-8456
Abstract
Mortalin/mtHsp70/Grp75 (mot-2), a heat shock protein 70 family member, is an essential chaperone, enriched in cancers, and has been shown to possess pro-proliferative and anti-apoptosis functions. An allelic form of mouse mortalin (mot-1) that differs by two amino acids, M618V and G624R, in the C terminus substrate-binding domain has been reported. Furthermore, genome sequencing of mortalin from Parkinson disease patients identified two missense mutants, R126W and P509S. In the present study, we investigated the significance of these mutations in survival, proliferation, and oxidative stress tolerance in human cells. Using mot-1 and mot-2 recombinant proteins and specific antibodies, we performed screening to find their binding proteins and then identified ribosomal protein L-7 (RPL-7) and elongation factor-1 alpha (EF-1 alpha), which differentially bind to mot-1 and mot-2, respectively. We demonstrate that mot-1, R126W, or P509S mutant (i) lacks mot-2 functions involved in carcinogenesis, such as p53 inactivation and hTERT/hnRNP-K (heterogeneous nuclear ribonucleoprotein K) activation; (ii) causes increased level of endogenous oxidative stress; (iii) results in decreased tolerance of cells to exogenous oxidative stress; and (iv) shows differential binding and impact on the RPL-7 and EF-1 alpha proteins. These factors may mediate the transformation of longevity/pro-proliferative function of mot-2 to the premature aging/anti-proliferative effect of mutants, and hence may have significance in cellular aging, Parkinson disease pathology, and prognosis.
URI
http://www.jbc.org/content/290/13/8447.shorthttp://hdl.handle.net/20.500.11754/22681
ISSN
0021-9258; 1083-351X
DOI
http://dx.doi.org/10.1074/jbc.M114.627463
Appears in Collections:
COLLEGE OF ENGINEERING[S](공과대학) > BIOENGINEERING(생명공학과) > Articles
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