Three-dimensional structure and regulation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs)

Angel Rivera-Calzada, Joseph D Maman, Joseph P Maman, Laura Spagnolo, Laurence H Pearl, Oscar Llorca

Research output: Contribution to journalArticlepeer-review

Abstract

DNA-PKcs is a large PI3-kinase-related protein kinase (PIKK) that plays a central role in DNA double-strand break (DSB) repair via nonhomologous end joining. Using cryo-electron microscopy we have now generated an approximately 13 A three-dimensional map of DNA-PKcs, revealing the overall architecture and topology of the 4128 residue polypeptide chain and allowing location of domains. The highly conserved C-terminal PIKK catalytic domain forms a central structure from which FAT and FATC domains protrude. Conformational changes observed in these domains on DNA binding suggest that they transduce DNA-induced conformational changes to the catalytic core and regulate kinase activity. The N-terminal segments form long curved tubular-shaped domains based on helical repeats to create interacting surfaces required for macromolecular assembly. Comparison of DNA-PKcs with another PIKK DNA repair factor, ATM, defines a common architecture for this important protein family.
Original languageEnglish
Pages (from-to)243-55
Number of pages13
JournalStructure
Volume13
Issue number2
DOIs
Publication statusPublished - 2005

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