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Similarity trap in protein-protein interactions could be carcinogenic: Simulations of p53 core domain complexed with 53BP1 and BRCA1 BRCT domains

  1. Author:
    Liu, J.
    Pan, Y. P.
    Ma, B. Y.
    Nussinov, R.

  2. Author Address

    SAIC Frederick Inc, Basic Res Program, Ctr Canc Res Nanobiol Program, NCI, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel.;Ma, BY, SAIC Frederick Inc, Basic Res Program, Ctr Canc Res Nanobiol Program, NCI, Frederick, MD 21702 USA.;mab@ncifcrf.gov ruthn@ncifcrf.gov
    1. Year: 2006
    2. Date: Dec
  2. Journal: Structure
    1. 14
    2. 12
    3. Pages: 1811-1821
  4. Type of Article: Article
  5. ISSN: 0969-2126
  1. 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 5313131 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.

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External Sources

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  2. DOI: 10.1016/j.str.2006.10.009
  3. View record in Web of Science®
  4. WOS: 000242888600009

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