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Science. 2014 Jul 18;345(6194):328-32. doi: 10.1126/science.1252943.

Human tRNA synthetase catalytic nulls with diverse functions.

Author information

1
IAS 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.
2
The Scripps Laboratories for tRNA Synthetase Research, The Scripps Research Institute, 10650 North Torrey Pines Road, La Jolla, CA 92037, USA. aTyr Pharma, 3545 John Hopkins Court, Suite 250, San Diego, CA 92121, USA.
3
aTyr Pharma, 3545 John Hopkins Court, Suite 250, San Diego, CA 92121, USA.
4
IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. The Scripps Laboratories for tRNA Synthetase Research, The Scripps Research Institute, 10650 North Torrey Pines Road, La Jolla, CA 92037, USA.
5
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
6
Department of Statistics, Stanford University, Stanford, CA 94305, USA.
7
The Scripps Laboratories for tRNA Synthetase Research, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
8
IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
9
IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. The Scripps Laboratories for tRNA Synthetase Research, The Scripps Research Institute, 10650 North Torrey Pines Road, La Jolla, CA 92037, USA. The Scripps Laboratories for tRNA Synthetase Research, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA. schimmel@scripps.edu.

Abstract

Genetic efficiency in higher organisms depends on mechanisms to create multiple functions from single genes. To investigate this question for an enzyme family, we chose aminoacyl tRNA synthetases (AARSs). They are exceptional in their progressive and accretive proliferation of noncatalytic domains as the Tree of Life is ascended. Here we report discovery of a large number of natural catalytic nulls (CNs) for each human AARS. Splicing events retain noncatalytic domains while ablating the catalytic domain to create CNs with diverse functions. Each synthetase is converted into several new signaling proteins with biological activities "orthogonal" to that of the catalytic parent. We suggest that splice variants with nonenzymatic functions may be more general, as evidenced by recent findings of other catalytically inactive splice-variant enzymes.

Comment in

PMID:
25035493
PMCID:
PMC4188629
DOI:
10.1126/science.1252943
[Indexed for MEDLINE]
Free PMC Article

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