title: The CDK5 repressor CDK5RAP1 is a methylthiotransferase acting on nuclear and mitochondrial RNA.
abstract: The unusual cyclin-dependent protein kinase 5 (CDK5) was discovered based on its sequence homology to cell cycle regulating CDKs. CDK5 was found to be active in brain tissues, where it is not involved in cell cycle regulation but in the regulation of neuronal cell differentiation and neurocytoskeleton dynamics. An aberrant regulation of CDK5 leads to the development of various neurodegenerative diseases including Alzheimer's disease. Although CDK5 is not regulated by cyclins, its activity does depend on the association with a protein activator and the presence or absence of further inhibitory factors. Recently, CDK5RAP1 was discovered to inhibit the active CDK5 kinase. Here, we show that CDK5RAP1 is a radical SAM enzyme, which postsynthetically converts the RNA modification N6-isopentenyladenosine (i(6)A) into 2-methylthio-N6-isopentenyladenosine (ms(2)i(6)A). This conversion is surprisingly not limited to mitochondrial tRNA, where the modification was known to exist. Instead, CDK5RAP1 introduces the modification also into nuclear RNA species establishing a link between postsynthetic kinase-based protein modification and postsynthetic RNA modification.
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Ludwig-Maximilians University, Munich 81377, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Reiter
authors.forename: Dorothea M S
authors.initials: DM
authors.lastname: Matschkal
authors.forename: Mirko
authors.initials: M
authors.lastname: Wagner
authors.forename: Daniel
authors.initials: D
authors.lastname: Globisch
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Kneuttinger
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Carell
mesh_terms: D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism*; D007541:Isopentenyladenosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D000077278:RNA, Mitochondrial; D012343:RNA, Transfer / Q000737:chemistry / Q000378:metabolism; D013466:Sulfurtransferases / Q000378:metabolism*; D019885:Sulfur Group Transferases; D024101:Mitochondrial Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007541:Isopentenyladenosine; D009419:Nerve Tissue Proteins; D012313:RNA; D000077278:RNA, Mitochondrial; D012343:RNA, Transfer; D013466:Sulfurtransferases; C008503:2-methylthio-N-6-isopentenyladenosine; C405930:CDK5RAP1 protein, human; D019885:Sulfur Group Transferases; D024101:Mitochondrial Proteins