TY - JOUR
T1 - MTG1 couples mitoribosome large subunit assembly with intersubunit bridge formation
AU - Kim, Hyun Jung
AU - Barrientos, Antoni
N1 - Funding Information:
National Institutes of Health (NIH) Medical Sciences Maximizing Investigator’s Award (NIGMS-MIRA) [R35GM118141 to A.B.]; Muscular Dystrophy Association Research Grant [MDA-381828 to A.B.]; American Heart Association Predoctoral Fellowship (to H.J.K). Funding for open access charge: NIH [R35GM118141]. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2018
PY - 2018/9/19
Y1 - 2018/9/19
N2 - Mammalian mitochondrial ribosomes (mitoribosomes) synthesize 13 proteins, essential components of the oxidative phosphorylation system. They are linked to mitochondrial disorders, often involving cardiomyopathy. Mitoribosome biogenesis is assisted by multiple cofactors whose specific functions remain largely uncharacterized. Here, we examined the role of human MTG1, a conserved ribosome assembly guanosine triphosphatase. MTG1-silencing in human cardiomyocytes and developing zebrafish revealed early cardiovascular lesions. A combination of gene-editing and biochemical approaches using HEK293T cells demonstrated that MTG1 binds to the large subunit (mtLSU) 16S ribosomal RNA to facilitate incorporation of late-assembly proteins. Furthermore, MTG1 interacts with mtLSU uL19 protein and mtSSU mS27, a putative guanosine triphosphate-exchange factor (GEF), to enable MTG1 release and the formation of the mB6 intersubunit bridge. In this way, MTG1 establishes a quality control checkpoint in mitoribosome assembly. In conclusion, MTG1 controls mitochondrial translation by coupling mtLSU assembly with intersubunit bridge formation using the intrinsic GEF activity acquired by the mtSSU through mS27, a unique occurrence in translational systems.
AB - Mammalian mitochondrial ribosomes (mitoribosomes) synthesize 13 proteins, essential components of the oxidative phosphorylation system. They are linked to mitochondrial disorders, often involving cardiomyopathy. Mitoribosome biogenesis is assisted by multiple cofactors whose specific functions remain largely uncharacterized. Here, we examined the role of human MTG1, a conserved ribosome assembly guanosine triphosphatase. MTG1-silencing in human cardiomyocytes and developing zebrafish revealed early cardiovascular lesions. A combination of gene-editing and biochemical approaches using HEK293T cells demonstrated that MTG1 binds to the large subunit (mtLSU) 16S ribosomal RNA to facilitate incorporation of late-assembly proteins. Furthermore, MTG1 interacts with mtLSU uL19 protein and mtSSU mS27, a putative guanosine triphosphate-exchange factor (GEF), to enable MTG1 release and the formation of the mB6 intersubunit bridge. In this way, MTG1 establishes a quality control checkpoint in mitoribosome assembly. In conclusion, MTG1 controls mitochondrial translation by coupling mtLSU assembly with intersubunit bridge formation using the intrinsic GEF activity acquired by the mtSSU through mS27, a unique occurrence in translational systems.
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U2 - 10.1093/nar/gky672
DO - 10.1093/nar/gky672
M3 - Article
C2 - 30085276
AN - SCOPUS:85061289792
VL - 46
SP - 8435
EP - 8453
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 16
ER -