A structural perspective on the PP-loop ATP pyrophosphatase family

Area of Science:

• Biochemistry and structural biology
• Enzymology
• Protein structure-function relationships

Background:

• The PP-loop ATP pyrophosphatase family, originating from ancient ATP-hydrolyzing proteins, utilizes a conserved "SxGxDS/T" motif for ATP binding and substrate adenylylation (AMPylation).
• Over 100 diverse PP-loop ATP pyrophosphatase structures are available, offering insights into conserved mechanisms and unique enzymatic reactions.

Purpose of the Study:

• To conduct a comprehensive database search for PP-loop ATP pyrophosphatase family members.
• To perform structure comparisons to identify common and variable structural features.
• To understand the structural basis for the diverse catalytic mechanisms within this enzyme superfamily.

Main Methods:

• Extensive database searching to identify and collect PP-loop ATP pyrophosphatase family members.
• Comparative structural analysis of representative enzyme structures.
• Identification of conserved core catalytic domains and variable regions.

Main Results:

• The most comprehensive collection of PP-loop ATP pyrophosphatase members to date, encompassing 18 enzyme families, was compiled.
• Structural comparison revealed conserved features in the core catalytic domain across the family.
• Four highly variable regions were identified, correlating with the unique chemistry of each enzyme family.

Conclusions:

• The study provides an updated and extensive catalog of the PP-loop ATP pyrophosphatase superfamily.
• Structural insights highlight conserved catalytic mechanisms and distinct features driving functional diversity.
• Newly identified enzymes, especially from pathogens, present opportunities for bioengineering and biomedical applications.