A robust approach for analyzing a heterogeneous structural ensemble.
Intrinsically unstructured proteins (IUP) are widespread in eukaryotes and participate in numerous cellular processes, but a structural explanation of the mechanisms they use to recognize and bind their diverse targets has proved elusive. Transcriptional activator domains are one class of IUP that function by recruiting other factors into basal transcription complexes. Transcriptional activator domains are known to use electrostatic interactions for recognition, but it is unclear how this could be accomplished by a structurally heterogeneous ensemble. To investigate this question, we performed principal component analysis on the atomic contact maps of an experimentally restrained ensemble of the human p53 transcriptional activator domain. This analysis revealed that the ensemble is conspicuously nonrandom and permitted a straightforward identification of persistent structural features and their relative probabilities. It was observed that six predominant long-range contacts are combinatorially arranged in 13 clusters of structures. Potential surfaces of the aligned clusters showed that these contacts uniformly organize the negative charges of the highly acidic p53 transcriptional activator domain on one face of the clusters. This observation provides a structural basis for the recruitment of other factors into basal transcription complexes and further supports the hypothesis that the structural ensembles of IUPs are not random and instead have evolved under selection to maintain specific structural features.
Lowry
David F
DF
Department of Microbiology, Molecular Biology, and Biochemistry, University of Idaho, Life Science South, Moscow, Idaho 83844-3052, USA.
Hausrath
Andrew C
AC
Daughdrill
Gary W
GW
D000595:Amino Acid Sequence; D016000:Cluster Analysis; D030562:Databases, Protein; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D025341:Principal Component Analysis / Q000379:methods*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D055672:Static Electricity; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
D016159:Tumor Suppressor Protein p53