A three-dimensional topology of complex I inferred from evolutionary correlations

Area of Science:

• Biochemistry
• Structural Biology
• Evolutionary Biology

Background:

• The quaternary structure of eukaryotic NADH:ubiquinone oxidoreductase (complex I), a key component of oxidative phosphorylation, remains largely undetermined.
• The precise interaction sites of transiently bound assembly factors with complex I are currently unknown.

Purpose of the Study:

• To investigate if evolutionary patterns within complex I can elucidate its 3D topology.
• To identify the binding positions of complex I assembly factors by analyzing evolutionary correlations.

Main Methods:

• Correlating evolutionary rates of eukaryotic complex I subunits using the mirror-tree method.
• Mapping evolutionary data into a 3D representation via multidimensional scaling.
• Developing a large evolutionary model incorporating 45 subunits and assembly factors.

Main Results:

• Over 60% of evolutionary correlation in the complex I matrix arm correlates with physical subunit distances, enabling accurate 3D modeling.
• The derived 3D evolutionary model of the matrix arm closely resembles that of Thermus thermophilus, supporting known eukaryotic structural differences from bacteria.
• The model predicts interactions of assembly factors NDUFAF3, C8orf38, and C2orf56, and suggests links between NUBPL/NDUFA2 and NDUFA12/NDUFAF2.

Conclusions:

• Physical subunit distances are significant correlates of protein evolution in the complex I matrix arm, sufficient for accurate structural inference.
• The developed evolutionary model successfully predicts the spatial arrangement of subunits and assembly factors within complex I.