Moonlighting Proteins: Some Hypotheses on the Structural Origin of Their Multifunctionality.

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Moonlighting proteins perform multiple functions, playing roles in human disease and microbial pathogenesis.
• Identifying these proteins is crucial for understanding disease mechanisms and developing therapies.
• The evolutionary pathways leading to protein multifunctionality remain largely unresolved.

Purpose of the Study:

• To investigate the structural mechanisms underlying the evolution of moonlighting proteins.
• To determine the prevalence of Non-Orthologous Gene Displacement/Non-Homologous Isofunctional Enzymes (NOGD/NHIE) and Fold-Switching Proteins (FSP) among human moonlighting proteins.

Main Methods:

• Analyzed the overlap between known human moonlighting proteins and curated datasets of NOGD/NHIE and FSPs.
• Employed Fisher's exact test for statistical validation of enrichment.

Main Results:

• Moonlighting proteins showed significant enrichment for NOGD/NHIE (19.89% vs. 0.39%, odds ratio = 63.1, p < 2.2 × 10^-16).
• Strong enrichment for FSPs was also observed (6.99% vs. 0.26%, odds ratio = 28.7, p = 1.13 × 10^-14).
• These findings indicate ~51-fold and ~27-fold higher risks for NOGD/NHIE and FSP features, respectively.

Conclusions:

• Intrinsic structural plasticity, via NOGD/NHIE or FSP mechanisms, is central to functional moonlighting in the human proteome.
• This plasticity facilitates functional innovation while maintaining sequence integrity.
• NOGD/NHIE and FSP features can serve as predictive signatures for novel moonlighting protein discovery, aiding disease mechanism and therapeutic targeting efforts.