1nzp

From Proteopedia

Revision as of 14:31, 15 February 2008

Solution Structure of the Lyase Domain of Human DNA Polymerase Lambda

Overview

DNA polymerase lambda (pol lambda) is a recently discovered nuclear enzyme, belonging to the pol X family of DNA polymerases that exhibits a 32%, sequence identity with the nuclear DNA repair protein, pol beta., Structural modeling suggests that pol lambda contains the palm, fingers, thumb, and 8 kDa lyase domains present in pol beta, as well as an, additional N-terminal BRCT domain and a serine-proline-rich linker that, are presumably involved in protein-protein interactions. The 8 kDa domain, of pol beta is important for DNA binding and contains the dRP lyase, activity, which is the rate-limiting step in the single-nucleotide base, excision repair (BER) pathway of damaged DNA. Recently, it was shown that, the 8 kDa domain of pol lambda also contains the dRP lyase activity. To, gain further insight into the catalytic mechanism of dRP removal by pol, lambda, we have determined the solution structure of the 8 kDa lyase, domain of human DNA pol lambda via multidimensional NMR methods and the, ARIA program. The resulting structures exhibited a high degree of, similarity with the 8 kDa lyase domain of pol beta. Specifically, the side, chains of residues W274, R275, Y279, K307, R308, and K312 are in similar, positions to the functionally important side chains of residues H34, K35, Y39, K60, K68, and K72 in the 8 kDa lyase domain of pol beta. This, suggests that, on the basis of the proposed roles of these residues in pol, beta, the corresponding pol lambda side chains may be involved in DNA, binding and dRP lyase activity. The structural alignment of W274 (pol, lambda) with H34 (pol beta) indicates that the former is probably involved, in a similar base stacking interaction with template DNA at the position, of the gap, in contrast with several previous proposals which aligned D272, with H34. In a few cases for which there is a nonconservative substitution, in the sequence alignment, a structural comparison shows a positionally, and, hence, probably a functionally equivalent residue, e.g., K60 in pol, beta and K307 in pol lambda. Additionally, on the basis of the structural, alignment obtained, several previously proposed mechanistic hypotheses can, be evaluated.

About this Structure

1NZP is a Single protein structure of sequence from Homo sapiens. Active as DNA-directed DNA polymerase, with EC number 2.7.7.7 Full crystallographic information is available from OCA.

Reference

Solution structure of the lyase domain of human DNA polymerase lambda., DeRose EF, Kirby TW, Mueller GA, Bebenek K, Garcia-Diaz M, Blanco L, Kunkel TA, London RE, Biochemistry. 2003 Aug 19;42(32):9564-74. PMID:12911298

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