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Human tRNA synthetase catalytic nulls with diverse functions.

Wing-Sze Lo1, Elisabeth Gardiner2, Zhiwen Xu1

  • 1IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Pangu Biopharma, Edinburgh Tower, The Landmark, 15 Queen's Road Central, Hong Kong, China.

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Higher organisms create gene efficiency by evolving aminoacyl tRNA synthetases (AARSs) into new signaling proteins. These splice variants retain noncatalytic domains, yielding diverse, nonenzymatic functions beyond their original catalytic roles.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Genetic efficiency in higher organisms relies on generating multiple functions from single genes.
  • Aminoacyl tRNA synthetases (AARSs) are an enzyme family known for accumulating noncatalytic domains throughout evolution.
  • Understanding AARS evolution sheds light on gene functional diversification.

Purpose of the Study:

  • To investigate the functional diversification of human aminoacyl tRNA synthetases (AARSs).
  • To identify and characterize natural catalytic nulls (CNs) derived from AARSs.
  • To explore the potential for nonenzymatic functions in AARS splice variants.

Main Methods:

  • Bioinformatic analysis to identify natural catalytic nulls (CNs) in human AARSs.
  • Splicing event analysis to understand domain retention and ablation.
  • Functional characterization of CNs to determine their biological activities.

Main Results:

  • Discovery of numerous natural catalytic nulls (CNs) for each human AARS.
  • Identification of splicing events that preserve noncatalytic domains while removing the catalytic domain.
  • Demonstration that CNs possess diverse biological functions distinct from their parent synthetases.
  • These CNs function as signaling proteins with activities orthogonal to the original catalytic function.

Conclusions:

  • Human AARSs can be converted into multiple signaling proteins through splicing events that create catalytic nulls (CNs).
  • These CNs exhibit diverse, nonenzymatic functions, suggesting a broader role for catalytically inactive splice variants.
  • The findings support the hypothesis that splice variants with nonenzymatic functions are a general mechanism for gene functional expansion.