A widespread family of heat-resistant obscure (Hero) proteins protect against protein instability and aggregation

Abstract

Proteins are typically denatured and aggregated by heat. Exceptions to this principle include highly disordered and heat-resistant proteins found in extremophiles, which help these organisms tolerate extreme conditions such as drying, freezing, and high salinity.In contrast, the functions of heat-soluble proteins in non-extremophilic organisms including humans remain largely unexplored. Here we report that heat-resistant obscure (Hero) proteins, which remain soluble after boiling at 95ºC, are widespread in Drosophila and humans. Hero proteins are hydrophilic and highly charged, and function to stabilize various "client" proteins, protecting them from denaturation even under stress conditions such as heat shock, desiccation, and exposure to organic solvents. Hero proteins can also block several different types of pathological protein aggregations in cells, and in Drosophila strains that model neurodegenerative diseases. Moreover, some Hero proteins extend lifespan of Drosophila. Our study reveals that organisms naturally use Hero proteins as molecular shields to stabilize protein functions, highlighting their biotechnological and therapeutic potential.We are grateful to Qinghua Liu for providing the plasmids for Dicer-2 and R2D2 expression, Connie Cepko for pCAGEN vector, Drosophila

BBLN-1 is essential for intermediate filament organization and apical membrane morphology

“…A final intriguing hypothesis is that BUBL-1 is involved in protein aggregation. C9orf16 was found in a search for highly heat-resistant proteins that remain soluble upon boiling (Tsuboyama et al, 2020). The identified proteins, termed 'Hero' for heat-resistant obscure proteins, were shown to protect different subsets of proteins from aggregation or denaturation under stress conditions (Tsuboyama et al, 2020).…”

“…C9orf16 was found in a search for highly heat-resistant proteins that remain soluble upon boiling (Tsuboyama et al, 2020). The identified proteins, termed 'Hero' for heat-resistant obscure proteins, were shown to protect different subsets of proteins from aggregation or denaturation under stress conditions (Tsuboyama et al, 2020). Indeed, C9orf16 is differentially expressed in diseases characterized by protein aggregation, including amyotrophic lateral sclerosis (ALS) (Nijssen et al, 2018), Alzheimer's (Kong et al, 2009), and Parkinson's disease (Kim et al, 2020).…”

Overview of the “biophysics in nano-space” session at the 57th annual meeting of the biophysical society of Japan

“…Kotaro Tsuboyama (The University of Tokyo) presented his recent finding on the new Hero protein family (Tsuboyama et al 2019). From the classical point of view, folding is a fundamental feature of the "protein."…”

The cell type‐specific ER membrane protein UGS148 is not essential in mice

“…These newly discovered peptides lack known conserved domains and thus have long been overlooked by functional predictions based on primary sequence analyses. Studies have also shown that a group of novel proteins, entirely consisting of intrinsically disordered regions, possesses outstanding molecular properties to inhibit the formation of disease‐related molecular aggregates or protect DNA from irradiation (Hashimoto et al, 2016; Tsuboyama et al, 2020). Interestingly, at least two of these "superdisordered" proteins maintain their molecular activity even after the random shuffling of their primary amino acid sequences (Tsuboyama et al, 2020), suggesting that the function of these superdisordered proteins is dependent on the composition of the amino acids rather than their primary sequences.…”

“…Studies have also shown that a group of novel proteins, entirely consisting of intrinsically disordered regions, possesses outstanding molecular properties to inhibit the formation of disease‐related molecular aggregates or protect DNA from irradiation (Hashimoto et al, 2016; Tsuboyama et al, 2020). Interestingly, at least two of these "superdisordered" proteins maintain their molecular activity even after the random shuffling of their primary amino acid sequences (Tsuboyama et al, 2020), suggesting that the function of these superdisordered proteins is dependent on the composition of the amino acids rather than their primary sequences. The functional independence of the amino acid sequences makes it difficult to predict the function of these proteins by conventional bioinformatics analyses.…”