@article{929b04833fac455ca56c827e9e495fdf,
title = "{"}Similarity Trap{"} in Protein-Protein Interactions Could Be Carcinogenic: Simulations of p53 Core Domain Complexed with 53BP1 and BRCA1 BRCT Domains",
abstract = "Similar binding sites often imply similar protein-protein interactions and similar functions; however, similar binding sites may also constitute traps for nonfunctional associations. How are similar sites distinguished to prevent misassociations? BRCT domains from breast cancer-susceptibility gene product BRCA1 and protein 53BP1 have similar structures yet different binding behaviors with p53 core domain. 53BP1-BRCT domain forms a stable complex with p53. In contrast, BRCA1-p53 interaction is weak or other mechanisms operate. To delineate the difference, we designed 13 BRCA1-BRCT mutants and computationally investigated the structural and stability changes compared to the experimental p53-53BP1 structure. Interestingly, of the 13, the 2 mutations that are cancerous and involve nonconserved residues are those that enforced p53 core domain binding with BRCA1-BRCT in a way similar to p53-53BP1 binding. Hence, falling into the {"}similarity trap{"} may disrupt normal BRCA1 and p53 functions. Our results illustrate how this trap is avoided in the native state.",
keywords = "CELLCYCLE, PROTEINS",
author = "Jin Liu and Yongping Pan and Buyong Ma and Ruth Nussinov",
note = "Funding Information: We thank Drs. C.-J. Tsai, K. Gunasekaran, H. Jang, and J. Zheng for helpful discussions and suggestions. Computations performed in this project were conducted using Biowulf cluster at the National Institutes of Health, Bethesda, MD ( http://biowulf.nih.gov ). This project has been funded in whole or in part with Federal funds from the National Cancer Institute (NCI), National Institutes of Health, under contract number NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. The publisher or recipient acknowledges right of the U.S. Government to retain a non-exclusive, royalty-free license in and to any copyright covering the article.",
year = "2006",
month = dec,
doi = "10.1016/j.str.2006.10.009",
language = "English",
volume = "14",
pages = "1811--1821",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "12",
}