Evidence for conformational flexibility in the Tat-TAR recognition motif of cyclin T1

Virology. 2004 Jan 5;318(1):306-17. doi: 10.1016/j.virol.2003.10.003.

Abstract

Cyclin T1 (CycT1) is a cellular transcription elongation factor that also participates in Tat-mediated activation of several lentiviral promoters. In human immunodeficiency virus (HIV), CycT1 is required for Tat to bind tightly to TAR and interacts in the ternary complex via its Tat-TAR recognition motif (TRM). In the related bovine immunodeficiency virus (BIV), Tat recognizes its cognate TAR element with high affinity and specificity in the absence of CycT1. At both promoters, CycT1 recruits the Cdk9 kinase, which phosphorylates RNA polymerase II to generate processive transcription complexes. To examine the physical properties of CycT1, we purified a functional domain corresponding to residues 1-272 and found that it possesses a stably folded core, as judged by partial proteolysis and circular dichroism experiments. Interestingly, the C-terminal 20 residues corresponding to the TRM appear conformationally flexible or disordered. The TRM of the bovine CycT1 (bCycT1) is similarly sensitive to proteolysis yet differs in sequence from the human protein. In particular, bCycT1 lacks a cysteine at residue 261 known to be critical for HIV but not BIV ternary complex formation, and mutagenesis data are consistent with a proposed role for this cysteine in metal binding. The apparent flexibility of the TRM suggests that conformational rearrangements may accompany formation of CycT1-Tat-TAR ternary complexes and may contribute to different TAR recognition strategies in different lentiviruses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cattle
  • Circular Dichroism
  • Cyclin T
  • Cyclins / chemistry*
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Gene Products, tat / metabolism*
  • HIV Long Terminal Repeat / physiology*
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Protein Conformation
  • Sequence Alignment
  • Species Specificity

Substances

  • CCNT1 protein, human
  • Ccnt1 protein, mouse
  • Cyclin T
  • Cyclins
  • Gene Products, tat

Associated data

  • GENBANK/AY428555