Intrinsically disordered regions of p53 family are highly diversified in evolution

Abstract

Proteins of the p53 family are expressed in vertebrates and in some invertebrate species. The main function of these proteins is to control and regulate cell cycle in response to various cellular signals, and therefore to control the organism’s development. The regulatory functions of the p53 family members originate mostly from their highly-conserved and well-structured DNA-binding domains. Many human diseases (including various types of cancer) are related to the missense mutations within this domain. The ordered DNA-binding domains of the p53 family members are surrounded by functionally important intrinsically disordered regions. In this study, substitution rates and propensities in different regions of p53 were analyzed. The analyses revealed that the ordered DNA-binding domain is conserved, whereas disordered regions are characterized by high sequence diversity. This diversity was reflected both in the number of substitutions and in the types of substitutions to which each amino acid was prone. These results support the existence of a positive correlation between protein intrinsic disorder and sequence divergence during the evolutionary process. This higher sequence divergence provides strong support for the existence of disordered regions in p53 in vivo for if they were structured, they would evolve at similar rates as the rest of the protein.

Introducing Protein Intrinsic Disorder

“…191,[193][194][195] It is to be noted, however, that binding regions within IDPs might correspond more to a domain than a motif, with their length exceeding 20-30 residues. 203 Indeed, these regions possess typical characteristics of domains: 1) they are structurally and functionally independent of the remainder of the protein molecule, 2) they can be recognized by homology due to evolutionary conservation of sequences, [204][205][206] and 3) they possess at least one specific function. In fact, about 14% of Pfam domains (i.e.…”

The Tail That Wags the Dog: How the Disordered C-Terminal Domain Controls the Transcriptional Activities of the p53 Tumor-Suppressor Protein

“…Their IDR characteristics have been confirmed by experimental and computational structure-prediction studies [13–15]. A substitution frequency analysis focusing on the NTD and the CTD of p53 revealed substantial differences between these two IDRs in relative distribution of polar, charged, and hydrophobic residues [16]. The multifunctional nature of the CTD is likely dependent on its IDR, which possesses a unique amino acid composition that dictates both intrinsic flexibility and the potential presence of regions known as molecular recognition features (MoRFs) (Box 2) [17,18].…”

“…By contrast, predicted MoRF sequences within both terminal p53 domains appear to be more conserved than the sequences of other non-DBD regions [16]. Based on the alignment data, there are at least two highly conserved subregions within the CTD that can be traced down to cartilaginous fish (Figure 2).…”

“…They possess natively disordered regions, although the degree of disorder across the p53 family varies significantly [26]. Computational disorder analysis identifies multiple IDRs within the longest isoforms of these proteins, TA p63∝ and TA p73∝, and predicts the presence of several corresponding MoRFs, some of which seem to coincide roughly with the related p53 MoRFs [16]. Nevertheless, the alignment of p53, p63, and p73 MoRF sequences shows little conservation, suggesting a diverse (although sometimes overlapping) set of interacting partners and different functions [16].…”

Using Integrated Bioinformatics Strategy to Identify Critical Factors for the Structural Integrity of Salmonella T3SS

“…PONDR-FIT is one of most accurate predictors for disorder prediction and for providing biologically relevant information [68] . The combination of PONDR-VLXT and PONDR-FIT was used by us to analyze the correlation between protein intrinsic disorder and function in many projects, such as reprogramming factors of induced ploripotent stem cells [69] , structural flexibility and mechanisms for methionine oxidation [70] , evolution of P53 [71] , PTEN interactome [72] , virulence factors [73] , yeast mitosis factors [74] , DBC1 [75] , Emerin [76] , etc. Both of these two predictors take amino acid sequence as input.…”