Structural analysis of human ATE1 isoforms and their interactions with Arg-tRNA_Arg

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Posttranslational protein arginylation regulates eukaryotic cellular processes by influencing protein stability, function, and macromolecular interactions.
• The enzyme Arginyltransferase (ATE1) and its targets are critical for modulating cellular functions in both normal and diseased states.
• Detailed structural information on human ATE1 (hATE1) isoforms has been lacking, hindering a full understanding of its role.

Purpose of the Study:

• To predict the overall structure of human ATE1 (hATE1) enzyme and its four isoforms.
• To investigate the structure-function relationship of hATE1 isoforms.
• To explore the implications of structural variations and non-synonymous single nucleotide polymorphisms (nsSNPs) on hATE1 function.

Main Methods:

• 3D structures of four hATE1 isoforms were computationally modeled.
• Molecular docking was performed between hATE1 isoforms and Arg-tRNAArg.
• Molecular dynamics (MD) simulations and Root Mean Square Fluctuation (RMSF) analysis were conducted.
• Non-synonymous single nucleotide polymorphisms (nsSNPs) were mined to assess their impact.

Main Results:

• All hATE1 isoforms exhibited two distinct domains: one compact and one flexible.
• Structural similarities were noted between hATE1-1/X4 and hATE1-2/5 isoforms.
• Active sites were conserved in location but differed in residues, suggesting varied substrate specificities.
• Deleterious nsSNPs, including cancer-associated ones, were identified, potentially impacting hATE1 structure and function.

Conclusions:

• This study provides the first structural insights into mammalian ATE1 isoforms, highlighting their differences.
• Structural variations among hATE1 isoforms likely contribute to distinct substrate specificities and cellular roles.
• Identified nsSNPs offer potential targets for understanding disease mechanisms and developing therapeutic strategies.