Abstract
Specific activation of amino acids by aminoacyl-tRNA synthetases (aaRSs) is essential for maintaining fidelity during protein translation. Here, we present crystal structure of malaria parasite Plasmodium falciparum tryptophanyl-tRNA synthetase (Pf-WRS) catalytic domain (AAD) at 2.6 Å resolution in complex with L-tryptophan. Confocal microscopy-based localization data suggest cytoplasmic residency of this protein. Pf-WRS has an unusual N-terminal extension of AlaX-like domain (AXD) along with linker regions which together seem vital for enzymatic activity and tRNA binding. Pf-WRS is not proteolytically processed in the parasites and therefore AXD likely provides tRNA binding capability rather than editing activity. The N-terminal domain containing AXD and linker region is monomeric and would result in an unusual overall architecture for Pf-WRS where the dimeric catalytic domains have monomeric AXDs on either side. Our PDB-wide comparative analyses of 47 WRS crystal structures also provide new mechanistic insights into this enzyme family in context conserved KMSKS loop conformations.
Highlights
Malaria is still a serious health risk despite numerous concerted programs that aim to control it
The N-terminal domain (NTD) of Pf-WRS is an extension of 227 residues which correspond to a domain spanning 1–155 and a linker region from 156–227 (Figure 1)
Pf-WRS AlaX-like domain (AXD) is unlike Type II AlaX modules which have an additional C-terminal domain meant for specific contacts with tRNAAla [32]
Summary
Malaria is still a serious health risk despite numerous concerted programs that aim to control it. Studies have revealed that aaRSs come in two flavors where each class shares sequence motifs and a similar topology in their catalytic domains [7], [8]. Class I aaRSs contain two conserved sequences - HIGH and KMSKS that trap ATP [7], [8]. Tryptophanyl-tRNA synthetase (WRS) is a class I aaRS and all members of this class are characterized by a Rossmann-fold catalytic domain whose active site is recognizable by the presence of consensus sequences HIGH and KMSKS [7]–[][9]. The active site of Pf-WRS exhibits a third weakly conserved motif GIDQ (AIDQ in the human sequence) that is involved in ATP binding. The key KMSKS loop has been found to be either ordered or disordered in individual crystal structures of WRSs from bacteria, human [10], [11]
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