title: A functional peptidyl-tRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome.
abstract: Bioinformatic analysis classifies the human protein encoded by immature colon carcinoma transcript-1 (ICT1) as one of a family of four putative mitochondrial translation release factors. However, this has not been supported by any experimental evidence. As only a single member of this family, mtRF1a, is required to terminate the synthesis of all 13 mitochondrially encoded polypeptides, the true physiological function of ICT1 was unclear. Here, we report that ICT1 is an essential mitochondrial protein, but unlike the other family members that are matrix-soluble, ICT1 has become an integral component of the human mitoribosome. Release-factor assays show that although ICT1 has retained its ribosome-dependent PTH activity, this is codon-independent; consistent with its loss of both domains that promote codon recognition in class-I release factors. Mutation of the GGQ domain common to ribosome-dependent PTHs causes a loss of activity in vitro and, crucially, a loss of cell viability, in vivo. We suggest that ICT1 may be essential for hydrolysis of prematurely terminated peptidyl-tRNA moieties in stalled mitoribosomes.
authors.affiliation: Mitochondrial Research Group, Institute for Ageing and Health, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Richter
authors.forename: Joanna
authors.initials: J
authors.lastname: Rorbach
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pajak
authors.forename: Paul M
authors.initials: PM
authors.lastname: Smith
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Wessels
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
authors.forename: Jan A
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Robert N
authors.initials: RN
authors.lastname: Lightowlers
authors.forename: Zofia M
authors.initials: ZM
authors.lastname: Chrzanowska-Lightowlers
mesh_terms: D000595:Amino Acid Sequence; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010454:Peptide Termination Factors / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012269:Ribosomal Proteins; D012270:Ribosomes / Q000378:metabolism*
chemical_list: C098021:MRPL58 protein, human; C523958:MTRF1L protein, human; D024101:Mitochondrial Proteins; D010454:Peptide Termination Factors; D011506:Proteins; D012269:Ribosomal Proteins; D002265:Carboxylic Ester Hydrolases; C019674:aminoacyl-tRNA hydrolase