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Structural Biology of the Human High Mobility Group A (HMGA) Proteins: Characterizing the Hub of Nuclear Function


EMSL Project ID
1620b

Abstract

The objective of this project is to provide new insight into the structural basis for some of the many biological processes involving the mammalian HMGA1 family of "high mobility group" (HMG) proteins. By themselves these small proteins (~ 100 amino acids) are unstructured in solution. However, in association with DNA and/or other proteins they form complexes that affect a wide variety of biological processes such as gene expression, neoplastic transformation, differentation, and apoptosis. One biological process involving HMGA1 is gene regulation by acting as an "architectural transcription factor", a protein that recognizes DNA structure rather than sequence. Presumably, allosteric changes to the DNA affected by HMGA1 binding increases the DNA binding affinity of other transcription factors. In turn, the transcription factors often bind to HMGA1 to form a new structure called an enhanceosome. High field nuclear magnetic resonance (NMR) spectrometers (up to 21.1 Tesla), powerful new NMR experiments, and versatile DNA and protein isotope labeling capabilities will be used to study the structure of DNA, HMGA92 (a fragment of HMGA1 missing the C-terminal 17 residues), and a transcription factor domain (Ets domain of human Elf-1) alone and in various pre-enhanceosome complex combinations. Extensive use will be made of residual dipolar coupling data to determine the structure of the DNA free in solution, in combination with HMGA92 and in combination with the Elf-1 Ets domain, and in combination with HMGA92 and the Elf-1 Ets domain. The DNA sequences used, at 21 and 20 base pairs, will be the longest yet studied in solution by NMR spectroscopy.

Project Details

Project type
Capability Research
Start Date
2005-04-11
End Date
2006-03-22
Status
Closed

Team

Principal Investigator

Raymond Reeves
Institution
Washington State University

Team Members

Garry Buchko
Institution
Pacific Northwest National Laboratory

Michael Kennedy
Institution
Miami University