title: Investigating the intrinsic aggregation potential of evolutionarily conserved segments in p53.
abstract: Protein aggregation and amyloid formation are known to play a role both in diseases and in biological functions. Transcription factor p53 plays a major role in tumor suppression by maintaining genomic stability. Recent studies have suggested that amyloid formation of p53 could lead to its loss of physiological function as a tumor suppressor. Here, we investigated the intrinsic amyloidogenic nature of wild-type p53 using sequence analysis. We used bioinformatics and aggregation prediction algorithms to establish the evolutionarily conserved nature of aggregation-prone sequences in wild-type p53. Further, we analyzed the amyloid forming capacity of conserved and aggregation-prone p53-derived peptides PILTIITL and YFTLQI in vitro using various biophysical techniques, including all atom molecular dynamics simulation. Finally, we probed the seeding ability of the PILTIITL peptide on p53 aggregation in vitro and in cells. Our data demonstrate the intrinsic amyloid forming ability of a sequence stretch of the p53 DNA binding domain (DBD) and its aggregation templating behavior on full-length and p53 core domain. Therefore, p53 aggregation, instigated through an amyloidogenic segment in its DBD, could be a putative driving force for p53 aggregation in vivo.
authors.affiliation: Department of Biosciences and Bioengineering, IIT Bombay , Powai, Mumbai 400076, India.
authors.forename: Saikat
authors.initials: S
authors.lastname: Ghosh
authors.forename: Dhiman
authors.initials: D
authors.lastname: Ghosh
authors.forename: Srivastav
authors.initials: S
authors.lastname: Ranganathan
authors.forename: A
authors.initials: A
authors.lastname: Anoop
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: P
authors.forename: Narendra Nath
authors.initials: NN
authors.lastname: Jha
authors.forename: Ranjith
authors.initials: R
authors.lastname: Padinhateeri
authors.forename: Samir K
authors.initials: SK
authors.lastname: Maji
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; D016159:Tumor Suppressor Protein p53; D004247:DNA