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Title: Crystal Structure of the BARD1 BRCT Domains

Abstract

The interaction of the breast tumor suppressor BRCA1 with the protein BARD1 results in the formation of a heterodimeric complex that has ubiquitin ligase activity and plays central roles in cell cycle checkpoint control and DNA repair. Both BRCA1 and BARD1 possess a pair of tandem BRCT domains that interact in a phosphorylation-dependent manner with target proteins. We determined the crystal structure of the human BARD1 BRCT repeats (residues 568-777) at 1.9 {angstrom} resolution. The composition and structure of the BARD1 phosphoserine-binding pocket P{sub 1} are strikingly similar to those of the BRCA1 and MDC1 BRCT domains, suggesting a similar mode of interaction with the phosphate group of the ligand. By contrast, the BARD1 BRCT selectivity pocket P{sub 2} exhibits distinct structural features, including two prominent histidine residues, His685 and His686, which may be important for ligand binding. The protonation state of these histidines has a marked effect on the calculated electrostatic potential in the vicinity of P{sub 2}, raising the possibility that ligand recognition may be regulated by changes in pH. Importantly, the BARD1 BRCT structure provides insights into the mechanisms by which the cancer-associated missense mutations C645R, V695L, and S761N may adversely affect the structure and function ofmore » BARD1.« less

Authors:
; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
929941
Report Number(s):
BNL-80536-2008-JA
Journal ID: ISSN 0006-2960; TRN: US200822%%1110
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemistry; Journal Volume: 46
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CELL CYCLE; CONTROL; CRYSTAL STRUCTURE; DNA REPAIR; ELECTROSTATICS; ELECTRIC POTENTIAL; FUNCTIONS; HISTIDINE; HUMAN POPULATIONS; INTERACTIONS; LIGANDS; LIGASES; MAMMARY GLANDS; MUTATIONS; NEOPLASMS; PHOSPHATES; PROTEINS; RESIDUES; national synchrotron light source

Citation Formats

Birrane,G., Varma, A., Soni, A., and Ladias, J. Crystal Structure of the BARD1 BRCT Domains. United States: N. p., 2007. Web. doi:10.1021/bi700323t.
Birrane,G., Varma, A., Soni, A., & Ladias, J. Crystal Structure of the BARD1 BRCT Domains. United States. doi:10.1021/bi700323t.
Birrane,G., Varma, A., Soni, A., and Ladias, J. Mon . "Crystal Structure of the BARD1 BRCT Domains". United States. doi:10.1021/bi700323t.
@article{osti_929941,
title = {Crystal Structure of the BARD1 BRCT Domains},
author = {Birrane,G. and Varma, A. and Soni, A. and Ladias, J.},
abstractNote = {The interaction of the breast tumor suppressor BRCA1 with the protein BARD1 results in the formation of a heterodimeric complex that has ubiquitin ligase activity and plays central roles in cell cycle checkpoint control and DNA repair. Both BRCA1 and BARD1 possess a pair of tandem BRCT domains that interact in a phosphorylation-dependent manner with target proteins. We determined the crystal structure of the human BARD1 BRCT repeats (residues 568-777) at 1.9 {angstrom} resolution. The composition and structure of the BARD1 phosphoserine-binding pocket P{sub 1} are strikingly similar to those of the BRCA1 and MDC1 BRCT domains, suggesting a similar mode of interaction with the phosphate group of the ligand. By contrast, the BARD1 BRCT selectivity pocket P{sub 2} exhibits distinct structural features, including two prominent histidine residues, His685 and His686, which may be important for ligand binding. The protonation state of these histidines has a marked effect on the calculated electrostatic potential in the vicinity of P{sub 2}, raising the possibility that ligand recognition may be regulated by changes in pH. Importantly, the BARD1 BRCT structure provides insights into the mechanisms by which the cancer-associated missense mutations C645R, V695L, and S761N may adversely affect the structure and function of BARD1.},
doi = {10.1021/bi700323t},
journal = {Biochemistry},
number = ,
volume = 46,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}