Structural impacts of two disease-linked ADAR1 mutants: a molecular dynamics study.

Area of Science:

• Molecular Biology
• Structural Biology
• Genetics

Background:

• Adenosine deaminases acting on RNA (ADARs) are crucial RNA-editing enzymes.
• ADAR1 editing dysregulation is implicated in autoinflammatory diseases due to genetic mutations.
• The structure of the ADAR1 deaminase domain is not experimentally determined, hindering mechanistic understanding.

Purpose of the Study:

• To computationally model the ADAR1 deaminase domain in wild-type and mutant forms.
• To investigate the structural basis of reduced deaminase activity in pathogenic variants.
• To elucidate the role of structural complementarity in ADAR1-dsRNA recognition.

Main Methods:

• Homology modeling
• AlphaFold2 for structural model construction
• Analysis of wild-type and two pathogenic ADAR1 variants (R892H, Y1112F)

Main Results:

• Structural models of ADAR1 deaminase domain (wild-type, R892H, Y1112F) were generated.
• Key residues (E1008, K1120) are critical for binding dsRNA by interacting with its minor and major grooves.
• Mutations R892H and Y1112F disrupt the position of K1120, impairing substrate RNA binding.

Conclusions:

• Structural complementarity between ADAR1 and dsRNA is vital for enzyme-substrate recognition.
• Specific mutations hinder ADAR1 activity by altering key structural interactions necessary for RNA binding.
• Understanding these structural impacts provides insights into ADAR1-related autoinflammatory diseases.