Human topoisomerase I C-terminal domain fragment containing the active site tyrosine is a molten globule: Implication for the formation of competent productive complex

Chandanamali Punchihewa, Jixun Dai, Megan Carver, Danzhou Yang

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Human topoisomerase I (topo I) is an essential cellular enzyme that relaxes DNA supercoiling. The 6.3 kDa C-terminal domain of topo I contains the active site tyrosine (Tyr723) but lacks enzymatic activity by itself. Activity can be fully reconstituted when the C-terminal domain is associated with the 56 kDa core domain. Even though several crystal structures of topo I/DNA complexes are available, crystal structures of the free topo I protein or its individual domain fragments have been difficult to obtain. In this report we analyze the human topo I C-terminal domain structure using a variety of biophysical methods. Our results indicate that this fragment protein (topo6.3) appears to be in a molten globule state. It appears to have a native-like tertiary fold that contains a large population of α-helix secondary structure and extensive surface hydrophobic regions. Topo6.3 is known to be readily activated with the association of the topo I core domain, and the molten globule state of topo6.3 is likely to be an energy-favorable conformation for the free topo I C-terminal domain protein. The structural fluctuation and plasticity may represent an efficient mechanism in the topo I functional pathway, where the flexibility aids in the complementary association with the core domain and in the formation of a fully productive topo I complex.

Original languageEnglish (US)
Pages (from-to)111-121
Number of pages11
JournalJournal of Structural Biology
Volume159
Issue number1
DOIs
StatePublished - Jul 1 2007

Keywords

  • CD
  • Fluorescence
  • Human topoisomerase I C-terminal domain
  • Molten globule
  • NMR

ASJC Scopus subject areas

  • Structural Biology

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