Solution structure and backbone dynamics of the human DNA ligase IIIα BRCT domain

Viswanathan V Krishnan, K. H. Thornton, M. P. Thelen, M. Cosman

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

BRCT (BRCA1 carboxyl terminus) domains are found in a number of DNA repair enzymes and cell cycle regulators and are believed to mediate important protein - protein interactions. The DNA ligase IIIα BRCT domain partners with the distal BRCT domain of the DNA repair protein XRCC1 (X1BRCTb) in the DNA base excision repair (BER) pathway. To elucidate the mechanisms by which these two domains can interact, we have determined the solution structure of human ligase IIIα BRCT (L3[86], residues 837-922). The structure of L3[86] consists of a β2β1β3β4 parallel sheet with a two-α-helix bundle packed against one face of the sheet. This fold is conserved in several proteins having a wide range of activities, including X1BRCTb [Zhang, X. D., et al. (1998) EMBO J. 17, 6404-641l]. L3[86] exists as a dimer in solution, but an insufficient number of NOE restraints precluded the determination of the homodimer structure. However, 13C isotope-filtered and hydrogen - deuterium exchange experiments indicate that the N-terminus, α1, the αl-β2 loop, and the three residues following α2 are involved in forming the dimer interface, as similarly observed in the structure of X1BRCTb. NOE and dynamic data indicate that several residues (837-844) in the N-terminal region appear to interconvert between helix and random coil conformations. Further studies of other BRCT domains and of their complexes are needed to address how these proteins interact with one another, and to shed light on how mutations can lead to disruption of function and ultimately disease.

Original languageEnglish (US)
Pages (from-to)13158-13166
Number of pages9
JournalBiochemistry
Volume40
Issue number44
DOIs
StatePublished - Nov 6 2001
Externally publishedYes

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DNA Ligases
Dimers
Proteins
DNA Repair Enzymes
Deuterium
Ligases
Isotopes
DNA Repair
Conformations
Hydrogen
Cell Cycle
Repair
Cells
Mutation
DNA Ligase ATP
DNA
Experiments

ASJC Scopus subject areas

  • Biochemistry

Cite this

Solution structure and backbone dynamics of the human DNA ligase IIIα BRCT domain. / Krishnan, Viswanathan V; Thornton, K. H.; Thelen, M. P.; Cosman, M.

In: Biochemistry, Vol. 40, No. 44, 06.11.2001, p. 13158-13166.

Research output: Contribution to journalArticle

Krishnan, Viswanathan V ; Thornton, K. H. ; Thelen, M. P. ; Cosman, M. / Solution structure and backbone dynamics of the human DNA ligase IIIα BRCT domain. In: Biochemistry. 2001 ; Vol. 40, No. 44. pp. 13158-13166.
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