Structural determinants of co-translational protein complex assembly

Area of Science:

• Molecular Biology
• Structural Biology
• Genetics

Background:

• Protein complex assembly is essential for biological functions.
• Co-translational assembly, occurring during protein synthesis, is increasingly recognized in human cells.
• The underlying mechanisms and specific protein partners involved in co-translational assembly are largely unknown.

Purpose of the Study:

• To elucidate the biological basis governing co-translational assembly.
• To identify protein pairs that undergo assembly during translation.
• To develop a predictive framework for co-translational assembly.

Main Methods:

• Analysis of structural characteristics of protein complexes.
• Utilizing AlphaFold2 predictions to identify structural signatures.
• Experimental validation using ribosome profiling, stoichiometry perturbations, and single-molecule RNA-fluorescence in situ hybridization (smFISH).

Main Results:

• Co-translational assembly is dictated by the structural properties of protein complexes.
• Subunits involved in co-translational assembly are unstable in isolation and mutually stabilize each other.
• Structural signatures and AlphaFold2 predictions accurately identified co-translational assembly pairs at a proteome-wide scale across species.

Conclusions:

• Established a fundamental link between protein three-dimensional structure and the translation process.
• Demonstrated the significant impact of structure on gene expression, mRNA localization, and proteostasis.
• Co-translational assembly is a structure-driven mechanism essential for cellular function.