Dimerization of the core domain of the p53 family: a computational study.
Computational models reveal the structural origins of cooperativity in the association of the DNA binding domains (DBD) of p53 (and its two homologues p63 and p73) with consensus DNA. In agreement with experiments they show that cooperativity, as defined by sequential binding of monomers to DNA is strong for p53 and weak for homologues p63 and p73. Computations also suggest that cooperativity can arise from the dimerization of the DBD prior to binding the DNA for all 3 family members. Dimerization between the DBDs is driven by packing interactions originating in residues of helix H1 and loop L3, while DNA binding itself is dominated by local and global electrostatics. Calculations further suggest that low affinity oligomerization of the p53 DBD can precede the oligomerization of the tetramerization domain (TD). During synthesis of multiple chains on the polysome, this may increase fidelity by reducing the possibility of the highly hydrophobic TD from nonspecific aggregation. Mutations have been suggested to test these findings.
Madhumalar
Arumugam
A
Bioinformatics Institute (A-STAR), 30 Biopolis Street, #07-01 Matrix, Singapore.
Jun
Lee Hui
LH
Lane
David P
DP
Verma
Chandra S
CS
D000595:Amino Acid Sequence; D019295:Computational Biology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013499:Surface Properties; D013816:Thermodynamics; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism
D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA