Transactivation domain of Adenovirus Early Region 1A (E1A): Investigating folding dynamics and aggregation

Abstract

Transactivation domain of Adenovirus Early region 1A (E1A) oncoprotein is an intrinsically disordered molecular hub protein. It is involved in binding to different domains of human cell transcriptional co-activators such as retinoblastoma (pRb), CREB-binding protein (CBP), and its paralogue p300. The conserved region 1 (TAD) of E1A is known to undergo structural transitions and folds upon interaction with transcriptional adaptor zinc finger 2 (TAZ2). Previous reports on Taz2-E1A studies have suggested the formation of helical conformations of E1A-TAD. However, the folding behavior of the TAD region in isolation has not been studied in detail. Here, we have elucidated the folding behavior of E1A peptide at varied temperatures and solution conditions. Further, we have studied the effects of macromolecular crowding on E1A-TAD peptide. Additionally, we have also predicted the molecular recognition features of E1A using MoRF predictors. The predicted MoRFs are consistent with its structural transitions observed during TAZ2 interactions for transcriptional regulation in literature. Also, as a general rule of MoRFs, E1A undergoes helical transitions in alcohol and osmolyte solution. Finally, we studied the aggregation behavior of E1A, where we observed that the E1A could form amyloid-like aggregates that are cytotoxic to mammalian cells.

Never Fold to Fold Continuously: A Conundrum in Ubiquitin–Proteasome System (UPS)-Mediated Protein Quality Control (PQC)

“…(IV) Molecular recognition effectors, which are understood to, upon binding to other proteins, modify their actions. Such IDPRs often undergo disorder-to-order conformational transition upon binding to their interacting partners' coupled folding and binding (i.e., WASP, p21, p27, DisUBM containing proteins, and adenovirus E1A oncoproteins) [23][24][25]. (V) Assemblers, which, as suggested by the name, interact with multiple binding partners, thereby bringing them together and thus encouraging and promoting the formation of higher-order protein complexes, such as members of the transcription preinitiation complex, ribosomes, and RIP1/RIP3 necrosomes [26][27][28].…”