Protein evolution and protein folding: non-functional conserved residues and their probable role

Area of Science:

• Biochemistry
• Structural Biology
• Protein Folding Dynamics

Background:

• Evolutionarily conserved residues in proteins are typically associated with function or structure.
• Two distinct classes of conserved residues have been identified in divergent, related proteins.
• The role of structure-related conserved residues in protein folding remains less understood.

Purpose of the Study:

• To characterize a newly identified group of conserved residues unrelated to protein function.
• To investigate the structural and folding implications of these non-functional conserved residues.
• To explore the potential role of these residues in protein folding initiation.

Main Methods:

• Comparative sequence analysis of evolutionary and functionally related proteins (c-type cytochromes and globins).
• Identification and localization of conserved residues within protein structures, specifically alpha-helices.
• Analysis of residue positions and interactions within helical structures and across different helical segments.

Main Results:

• Discovery of a second class of conserved residues not involved in protein active sites.
• Identification of 4 such residues in c-type cytochromes and 6 in globins, located within alpha-helices.
• These residues stabilize helical turns and form interfaces between helices, observed to form early and remain stable during folding intermediates.

Conclusions:

• The identified conserved residues are critical for protein structure and folding, not function.
• These residues likely contribute to the formation of stable helical complexes.
• These helical complexes are hypothesized to act as nucleation sites in the nucleation-growth mechanism of protein folding.