The accessory subunit of mtDNA polymerase shares structural homology with aminoacyl-tRNA synthetases: implications for a dual role as a primer recognition factor and processivity clamp.

Abstract:

The accessory subunit of the heterodimeric mtDNA polymerase (polgamma) from Drosophila embryos is required to maintain the structural integrity or catalytic efficiency of the holoenzyme. cDNAs for the accessory subunit from Drosophila, man, mouse, and rat have been identified, and comparative sequence alignment reveals that the C-terminal region of about 120 aa is the most conserved. Furthermore, we demonstrate that the accessory subunit of animal polgamma has both sequence and structural similarity with class IIa aminoacyl-tRNA synthetases. Based on sequence similarity and fold recognition followed by homology modeling, we have developed a model of the three-dimensional structure of the C-terminal region of the accessory subunit of polgamma. The model reveals a rare five-stranded beta-sheet surrounded by four alpha-helices with structural homology to the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases. We postulate that the accessory subunit plays a role in the recognition of RNA primers in mtDNA replication, to recruit polgamma to the template-primer junction. A similar role is served by the gamma-complex in Escherichia coli DNA polymerase III, and indeed our accessory subunit model shows structural similarity with the N-terminal domain of the delta' subunit of the gamma-complex. Structural similarity is also found with E. coli thioredoxin, the accessory subunit and processivity factor in bacteriophage T7 DNA polymerase. Thus, we propose that the accessory subunit of polgamma is involved both in primer recognition and in processive DNA strand elongation.

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