title: Functional significance of point mutations in stress chaperone mortalin and their relevance to Parkinson disease.
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 α (EF-1α), 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-1α 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.
authors: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine (DAILAB), Tsukuba, Ibaraki 305-8562, Japan and.
authors: Renu
authors: R
authors: Wadhwa
authors: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine (DAILAB), Tsukuba, Ibaraki 305-8562, Japan and the Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-Ro, Seongdong-Gu, Seoul 133-791, Korea.
authors: Jihoon
authors: J
authors: Ryu
authors: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine (DAILAB), Tsukuba, Ibaraki 305-8562, Japan and the Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-Ro, Seongdong-Gu, Seoul 133-791, Korea.
authors: Hyo Min
authors: HM
authors: Ahn
authors: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine (DAILAB), Tsukuba, Ibaraki 305-8562, Japan and.
authors: Nishant
authors: N
authors: Saxena
authors: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine (DAILAB), Tsukuba, Ibaraki 305-8562, Japan and.
authors: Anupama
authors: A
authors: Chaudhary
authors: the Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-Ro, Seongdong-Gu, Seoul 133-791, Korea chaeok@hanyang.ac.kr.
authors: Chae-Ok
authors: CO
authors: Yun
authors: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine (DAILAB), Tsukuba, Ibaraki 305-8562, Japan and s-kaul@aist.go.jp.
authors: Sunil C
authors: SC
authors: Kaul
mesh_terms: D021581:Active Transport, Cell Nucleus; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D024101:Mitochondrial Proteins / Q000502:physiology; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000235:genetics*; D017354:Point Mutation
chemical_list: D018840:HSP70 Heat-Shock Proteins; C492001:HSPA9 protein, human; D024101:Mitochondrial Proteins; C080352:mortalin
keywords: 70-kilodalton Heat Shock Protein (Hsp70); EF-1alpha; Mechanism; Mortalin; Oxidative Stress; Parkinson Disease; Point Mutation; Proliferation; Protein-Protein Interaction; RPL-7; Senescence
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