Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds.
The p53 family of proteins is comprised of p53, p63 and p73. Because the p53 DNA binding domain (DBD) is naturally unstable and possesses an amyloidogenic sequence, it is prone to form amyloid fibrils, causing loss of functions. To develop p53 therapies, it is necessary to understand the molecular basis of p53 instability and aggregation. Light scattering, thioflavin T (ThT) and high hydrostatic pressure (HHP) assays showed that p53 DBD aggregates faster and to a greater extent than p63 and p73 DBDs, and was more susceptible to denaturation. The aggregation tendencies of p53, p63, and p73 DBDs were strongly correlated with their thermal stabilities. Molecular Dynamics (MD) simulations indicated specific regions of structural heterogeneity unique to p53, which may be promoted by elevated incidence of exposed backbone hydrogen bonds (BHBs). The results indicate regions of structural vulnerability in the p53 DBD, suggesting new targetable sites for modulating p53 stability and aggregation, a potential approach to cancer therapy.
Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, RJ, Brazil.
Elio A
EA
Cino
Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, RJ, Brazil.
Iaci N
IN
Soares
Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, RJ, Brazil.
Murilo M
MM
Pedrote
Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, RJ, Brazil.
Guilherme A P
GA
de Oliveira
Programa de Biologia Estrutural, Instituto de Bioquímica Médica Leopoldo de Meis, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, RJ, Brazil.
Jerson L
JL
Silva
D000595:Amino Acid Sequence; D006801:Humans; D006860:Hydrogen Bonding; D005810:Multigene Family; D011312:Pressure; D066329:Protein Aggregates; D011489:Protein Denaturation; D000072417:Protein Domains; D055550:Protein Stability; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D066329:Protein Aggregates; D016159:Tumor Suppressor Protein p53