A paradigm shift for the amino acid editing mechanism of human cytoplasmic leucyl-tRNA synthetase.

Full Abstract

Leucyl-tRNA synthetase (LeuRS) has been identified as a target for a novel class of boron-containing small molecules that bind to its editing active site. When the 3' end of tRNA(Leu) binds to the editing active site, the boron cross-links to the cis-diols of its terminal ribose. The cross-linked RNA-protein complex blocks the overall aminoacylation activity of the enzyme. Similar to those of other LeuRSs, the human cytoplasmic enzyme (hscLeuRS) editing active site resides in a discrete domain called the connective polypeptide 1 domain (CP1), where mischarged tRNA binds for hydrolysis of the noncognate amino acid. The editing site of hscLeuRS includes a highly conserved threonine discriminator and universally conserved aspartic acid that were mutationally characterized. Substitution of the threonine residue to alanine uncoupled specificity as in other LeuRSs. However, the introduction of bulky residues into the amino acid binding pocket failed to block deacylation of tRNA, indicating that the architecture of the amino acid binding pocket is different compared to that of other characterized LeuRSs. In addition, mutation of the universally conserved aspartic acid abolished tRNA(Leu) deacylation. Surprisingly though, this editing-defective hscLeuRS maintained fidelity. It is possible that an alternate editing mechanism may have been activated upon failure of the post-transfer editing active site.

Author information

Author/s: Pang, Yan Ling Joy (YL); Martinis, Susan A (SA);

Affiliation: Department of Biochemistry, University of Illinois, 419 Roger Adams Laboratory, Box B-4, 600 South Matthews Avenue, Urbana, Illinois 61801, USA.

Grants: GM063789 (Agency:NIGMS NIH HHS)

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural

Journal: Biochemistry (Biochemistry), published in United States. (Language: eng)

Reference: 2009-Sep; vol 48 (issue 38) : pp 8958-64

Dates: Created 2009/09/22; Completed 2009/10/09;

PMID: 19702327, status: MEDLINE (last retrieval date: 10/9/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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