'Indirect Readout' Mediation of Protein-DNA Interactions

Project: Research project

Project Details

Description

The ability of proteins to recognize and bind specific sequences of DNA is a critical part of cellular function and regulation. Extensive structural and thermodynamic studies have yielded a general understanding of how direct contacts mediate the sequence-specific binding of proteins to DNA. However, subtle differences in DNA structure and dynamics often play critical roles in mediating the protein-DNA interactions that regulate many cellular processes by mechanisms independent of direct protein-DNA contacts. A regulatory system utilizing such an indirect control mechanism is the sequence-specific DNA binding by the papillomavirus E2 proteins. The E2 protein maintains a fine balance between replication and gene transcription that is essential for the viral life cycle; infection by some human papillomavirus strains is directly linked to cervical cancer. The regulation of papillomavirus replication and viral gene transcription is dependent upon E2 protein binding to an array of sites within viral genomes. The structure and dynamics of the DNA located within E2 protein binding sites is a principal determinant of protein binding affinity. The proposed studies use the E2 protein-DNA interaction as a model system to determine the mechanism by which local DNA structure and dynamics regulates sequence-specific binding. The foundation for the proposed thermodynamic and structural studies is the ensemble of atomic resolution structures of free protein, free DNA and protein-DNA complexes for the E2 family of evolutionarily related proteins that differ in their sensitivity to DNA structure and dynamics. The availability of these structures provides a unique opportunity to develop quantitative structure-function correlations regarding the indirect effect of conformational propensities of DNA upon protein binding in a context where direct protein-DNA interactions are kept constant.
StatusFinished
Effective start/end date9/1/018/31/02

Funding

  • National Institute of General Medical Sciences: $273,664.00

ASJC

  • Genetics
  • Molecular Biology
  • Structural Biology
  • Biophysics
  • Biochemistry

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