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Crystal structure of the BARD1 BRCT domains
Gabriel Birrane1, Ashok K Varma, Aditi Soni
1Molecular Medicine Laboratory and Macromolecular Crystallography Unit, Division of Experimental Medicine, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Biochemistry
|June 7, 2007
Summary
The BARD1 BRCT structure reveals similarities to BRCA1, suggesting a shared mechanism for DNA repair and cell cycle control. Distinct features in BARD1 may regulate ligand binding and explain cancer-associated mutations.
Area of Science:
- Biochemistry
- Structural Biology
- Cancer Biology
Background:
- The BRCA1-BARD1 complex is crucial for DNA repair and cell cycle control.
- Both proteins feature tandem BRCT domains involved in protein interactions.
Purpose of the Study:
- To determine the crystal structure of human BARD1 BRCT repeats.
- To elucidate the structural basis for BARD1's role in DNA repair and its interaction with BRCA1.
Main Methods:
- X-ray crystallography of human BARD1 BRCT repeats (residues 568-777).
- Analysis of structural similarities and differences with BRCA1 and MDC1 BRCT domains.
Main Results:
- The BARD1 BRCT structure shows a phosphoserine-binding pocket (P1) similar to BRCA1 and MDC1.
- BARD1's selectivity pocket (P2) has unique features, including histidine residues (His685, His686), potentially influencing ligand binding.
- The structure offers insights into how cancer-associated mutations affect BARD1 function.
Conclusions:
- BARD1 BRCT domains share structural and functional similarities with BRCA1, particularly in phosphoserine binding.
- Unique BARD1 P2 pocket features, possibly pH-regulated, may dictate specific ligand interactions.
- The determined structure aids in understanding the molecular basis of BARD1 dysfunction in cancer.
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