Mettl15-Mettl17 modulates the transition from early to late pre-mitoribosome

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Mitochondrial ribosome (mitoribosome) small subunit assembly requires rRNA folding, modification, and protein association.
• Assembly factors, including methyltransferases Mettl15 and Mettl17, guide this complex process.
• The distinct roles of Mettl17 (early stage) and Mettl15 (late stage) and their transition mechanism were not fully understood.

Purpose of the Study:

• To elucidate the mechanism by which Mettl15 and Mettl17 cooperate in mitoribosome small subunit assembly.
• To reveal the interplay between Mettl17 and Mettl15 in linking early and late assembly stages.
• To provide a structural basis for understanding the dynamic regulation of mitoribosome biogenesis.

Main Methods:

• Integration of structural data from *Trypanosoma brucei* and mammalian homologs.
• Molecular dynamics simulations.
• Biochemical analysis of methyltransferase function and substrate interaction.

Main Results:

• A model where Mettl17 acts as a platform for Mettl15 recruitment.
• Demonstration of Mettl17 release enabling Mettl15 conformational change and substrate recognition.
• Characterization of Mettl15's loosely bound state post-methylation, leading to its replacement by initiation factors.

Conclusions:

• Mettl15 and Mettl17 cooperatively regulate mitoribosome biogenesis through a sequential recruitment and release mechanism.
• The study provides a structural resource for understanding molecular adaptations of mitoribosome assembly factors.
• This work clarifies the transition between early and late stages of small subunit assembly.