title: Functional Diversity of Human Mitochondrial J-proteins Is Independent of Their Association with the Inner Membrane Presequence Translocase.
abstract: Mitochondrial J-proteins play a critical role in governing Hsp70 activity and, hence, are essential for organellar protein translocation and folding. In contrast to yeast, which has a single J-protein Pam18, humans involve two J-proteins, DnaJC15 and DnaJC19, associated with contrasting cellular phenotype, to transport proteins into the mitochondria. Mutation in DnaJC19 results in dilated cardiomyopathy and ataxia syndrome, whereas expression of DnaJC15 regulates the response of cancer cells to chemotherapy. In the present study we have comparatively assessed the biochemical properties of the J-protein paralogs in relation to their association with the import channel. Both DnaJC15 and DnaJC19 formed two distinct subcomplexes with Magmas at the import channel. Knockdown analysis suggested an essential role for Magmas and DnaJC19 in organellar protein translocation and mitochondria biogenesis, whereas DnaJC15 had dispensable supportive function. The J-proteins were found to have equal affinity for Magmas and could stimulate mitochondrial Hsp70 ATPase activity by equivalent levels. Interestingly, we observed that DnaJC15 exhibits bifunctional properties. At the translocation channel, it involves conserved interactions and mechanism to translocate the precursors into mitochondria. In addition to protein transport, DnaJC15 also showed a dual role in yeast where its expression elicited enhanced sensitivity of cells to cisplatin that required the presence of a functional J-domain. The amount of DnaJC15 expressed in the cell was directly proportional to the sensitivity of cells. Our analysis indicates that the differential cellular phenotype displayed by human mitochondrial J-proteins is independent of their activity and association with Magmas at the translocation channel.
authors.affiliation: From the Department of Biochemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India.
authors.forename: Devanjan
authors.initials: D
authors.lastname: Sinha
authors.affiliation: From the Department of Biochemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India.
authors.forename: Shubhi
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: From the Department of Biochemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India patrick@biochem.iisc.ernet.in.
authors.forename: Patrick
authors.initials: P
authors.lastname: D'Silva
mesh_terms: D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology
chemical_list: C519405:DNAJC15 protein, human; C511724:DNAJC19 protein, human; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; C503439:PAM16 protein, human
keywords: 70-kilodalton heat shock protein (Hsp70); J-protiens; chaperone DnaJ (DnaJ); import motor; mitochondria; mitochondrial transport; molecular chaperone; mtHsp70; protein folding