Protein function from its emergence to diversity in contemporary proteins

Area of Science:

• Biochemistry and Molecular Biology
• Evolutionary Biology
• Structural Biology
• Protein Engineering

Background:

• Protein structure and function are governed by fundamental physical laws and evolutionary processes.
• Understanding the origins of protein function can provide insights into enzyme evolution and design.
• Early life likely utilized simple functional units that evolved into complex enzymes.

Purpose of the Study:

• To identify ancient elementary functions (EFs) that served as building blocks for the first enzymes.
• To understand how combinations of EFs explain the diversity of contemporary enzymes.
• To establish rules for protein design by analyzing evolutionary relationships and conserved EFs.

Main Methods:

• Analysis of protein sequences to identify shared elementary functions (EFs) across diverse protein superfamilies and folds.
• Tracing evolutionary relationships between protein folds and functional superfamilies.
• Defining elementary functional loops as basic structural and functional units of biochemical reactions.

Main Results:

• Contemporary proteins are constructed from a limited repertoire of EFs, many originating from the prebiotic world.
• Metal and nucleotide cofactor binding/metabolism represent ancient and abundant EFs.
• Evolutionary analysis revealed conserved EFs shared by unrelated protein families, indicating common ancestry.
• Highly designable protein folds serve as scaffolds for diverse biochemical reactions.

Conclusions:

• The diversity of enzyme function can be explained by combinations of a limited set of EFs.
• Studying EFs provides a framework for understanding protein evolution and establishing principles for protein design.
• Generalized sequence-structure descriptors of EFs will be valuable for future enzyme engineering and the creation of novel enzymatic functions.