The Molecular Architecture of the Mammalian DNA Repair Enzyme, Polynucleotide Kinase
2005; Elsevier BV; Volume: 17; Issue: 5 Linguagem: Inglês
10.1016/j.molcel.2005.02.012
ISSN1097-4164
AutoresNina Bernstein, R. Scott Williams, M.L. Rakovszky, Diana Cui, Ruth Green, Feridoun Karimi‐Busheri, Rajam S. Mani, Sarah Galicia, Christine Koch, Carol E. Cass, Daniel Durocher, Michael Weinfeld, J. N. Mark Glover,
Tópico(s)Cancer-related Molecular Pathways
ResumoMammalian polynucleotide kinase (PNK) is a key component of both the base excision repair (BER) and nonhomologous end-joining (NHEJ) DNA repair pathways. PNK acts as a 5'-kinase/3'-phosphatase to create 5'-phosphate/3'-hydroxyl termini, which are a necessary prerequisite for ligation during repair. PNK is recruited to repair complexes through interactions between its N-terminal FHA domain and phosphorylated components of either pathway. Here, we describe the crystal structure of intact mammalian PNK and a structure of the PNK FHA bound to a cognate phosphopeptide. The kinase domain has a broad substrate binding pocket, which preferentially recognizes double-stranded substrates with recessed 5' termini. In contrast, the phosphatase domain efficiently dephosphorylates single-stranded 3'-phospho termini as well as double-stranded substrates. The FHA domain is linked to the kinase/phosphatase catalytic domain by a flexible tether, and it exhibits a mode of target selection based on electrostatic complementarity between the binding surface and the phosphothreonine peptide.
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