Crystal structure of tetrameric form of human lysyl-tRNA synthetase: Implications for multisynthetase complex formation

Journal Article · Wed Sep 17 04:00:00 EDT 2008 · Proc. Natl. Acad. Sci. USA

DOI:https://doi.org/10.1073/pnas.0712072105· OSTI ID:1006805

Guo, Min; Ignatov, Michael; Musier-Forsyth, Karin; Schimmel, Paul; Yang, Xiang-Lei ^[1]

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1. OSU

In mammals, many aminoacyl-tRNA synthetases are bound together in a multisynthetase complex (MSC) as a reservoir of procytokines and regulation molecules for functions beyond aminoacylation. The {alpha}{sub 2} homodimeric lysyl-tRNA synthetase (LysRS) is tightly bound in the MSC and, under specific conditions, is secreted to trigger a proinflammatory response. Results by others suggest that {alpha}{sub 2} LysRS is tightly bound into the core of the MSC with homodimeric {beta}{sub 2} p38, a scaffolding protein that itself is multifunctional. Not understood is how the two dimeric proteins combine to make a presumptive {alpha}{sub 2}{beta}{sub 2} heterotetramer and, in particular, the location of the surfaces on LysRS that would accommodate the p38 interactions. Here we present a 2.3-{angstrom} crystal structure of a tetrameric form of human LysRS. The relatively loose (as seen in solution) tetramer interface is assembled from two eukaryote-specific sequences, one in the catalytic- and another in the anticodon-binding domain. This same interface is predicted to provide unique determinants for interaction with p38. The analyses suggest how the core of the MSC is assembled and, more generally, that interactions and functions of synthetases can be built and regulated through dynamic protein-protein interfaces. These interfaces are created from small adaptations to what is otherwise a highly conserved (through evolution) polypeptide sequence.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1006805
• Journal Information: Proc. Natl. Acad. Sci. USA, Journal Name: Proc. Natl. Acad. Sci. USA Journal Issue: (7) ; 02, 2008 Vol. 105; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CRYSTAL STRUCTURE
LIGASES
MAMMALS
POLYPEPTIDES
PROTEINS
REGULATIONS