Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity

Abstract

In his Nobel Lecture, Anfinsen stated Bthe native conformation is determined by the totality of interatomic interactions and hence by the amino acid sequence, in a given environment.^As aqueous solutions and membrane systems co-exist in cells, proteins are classified into membrane and non-membrane proteins, but whether one can transform one into the other remains unknown. Intriguingly, many well-folded non-membrane proteins are converted into Binsoluble^and toxic forms by aging-or diseaseassociated factors, but the underlying mechanisms remain elusive. In 2005, we discovered a previously unknown regime of proteins seemingly inconsistent with the classic BSalting-in^dogma: Binsoluble^proteins including the integral membrane fragments could be solubilized in the ion-minimized water. We have thus successfully studied Binsoluble^forms of ALScausing P56S-MSP, L126Z-SOD1, nascent SOD1 and C71G-Profilin1, as well as E. coli S1 fragments. The results revealed that these Binsoluble^forms are either unfolded or co-exist with their unfolded states. Most unexpectedly, these unfolded states acquire a novel capacity of interacting with membranes energetically driven by the formation of helices/loops over amphiphilic/ hydrophobic regions which universally exit in proteins but are normally locked away in their folded native states. Our studies suggest that most, if not all, proteins contain segments which have the dual ability to fold into distinctive structures in aqueous and membrane environments. The abnormal membrane interaction might initiate disease and/or aging processes; and its further coupling with protein aggregation could result in radical proteotoxicity by forming inclusions composed of damaged membranous organelles and protein aggregates. Therefore, environment-transformable sequence-structure relationship may represent a general mechanism for proteotoxicity.

Adenosine triphosphate energy‐independently controls protein homeostasis with unique structure and diverse mechanisms

“…Now it becomes established that based on amino acid sequences, proteins encoded by higher eukaryotic genomes can in fact be grouped into two major categories: random and high‐complexity (I of Figure 1(a)), and non‐random and low‐complexity (II of Figure 1(a)) sequences. Only a portion of the first category can spontaneously fold into unique three‐dimensional structures but the mechanisms still remain not completely understood, particularly for the role of protein hydration despite exhaustive studies 2–9 . On the other hand, many proteins in the second category remain highly disordered but are functional (Figure 1(a)), thus designated as intrinsically disordered proteins (IDPs), and ~ 44% of human proteins contain intrinsically disordered regions (IDRs) of >30 amino acids 9–11 …”

“…Intriguingly, many proteins in both categories are prone to aggregation or even insoluble in cells or salted aqueous solution (Figure 1(a)), which is not only problematic for protein research and industry applications, but also associated with aging and an increasing spectrum of human disease, particularly neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), spinocerebellar ataxias (SCA), amyotrophic lateral sclerosis (ALS) 8,9,19,22–25 . IDR‐rich proteins are particularly prone to aggregation in the phase separated state because protein concentrations in droplets are 50–300 fold higher than those in the surrounding environments.…”

Misfolded proteins share a common capacity in disrupting LLPS organizing membrane-less organelles

“…If they also cannot be rapidly degraded, they might become irreversibly co-precipitated with other SG components driven by non-specific hydrophobic interactions between the recruited misfolded proteins and the exposed hydrophobic regions of SG proteins as previously reported on TDP-43 (15,16); or/and self-associated and aggregated which can be significantly accelerated by the high local concentrations of misfolded proteins within the liquid droplets because all misfolded/unfolded proteins are aggregation-prone (4,8,(46)(47)(48). As a consequence, the structures, dynamics and functions of SGs might be disrupted or even destroyed by misfolded proteins, and this will manifest as gain of toxicity for misfolded proteins.…”

“…Moreover, under certain stress conditions, misfolded proteins are largely generated, and thus not all of them can be efficiently refolded by chaperones. In particular, for patients carrying disease-causing genetic variations, the unfolded states of these mutants are no longer refoldable due to the loss of their intrinsic capacity to completely fold as exemplified by L126Z-SOD1 and C71G-PFN1 (47,48). As a result, these misfolded/unfolded proteins will become significantly accumulated within SGs.…”

Foreword to ‘Multiscale structural biology: biophysical principles and mechanisms underlying the action of bio-nanomachines’, a special issue in Honour of Fumio Arisaka’s 70th birthday

“…11). It is in honour of this service that we have contributions from a number of fellow APPA council members (North et al 2018;Tayo 2017;Sawitri et al 2018;Song 2018;Goto et al 2018).…”