Stability and Local Unfolding of SOD1 in the Presence of Protein Crowders

Bille, Anna; Jensen, Kim Degn; Mohanty, Sandipan; Akke, Mikael; Irbäck, Anders

doi:10.1021/acs.jpcb.8b10774

Cited by 22 publications

(26 citation statements)

References 60 publications

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“…However, the SOD1 β -barrel is generally destabilised by the cellular environment when compared with purified protein in aqueous buffer. In some cases, this can reduce its folding transition temperature by 40% (Danielsson et al ., 2015; Bille et al ., 2019). The change in stability conferred by the environment occurs through interactions with β -strands 6 and 8 that stabilise the unfolded state (Bille et al ., 2019).…”

Section: Sod1 Maturation and Als Mutantsmentioning

confidence: 99%

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Wright

Antonyuk

Hasnain

2019

Quart. Rev. Biophys.

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Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in thesod1gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.

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Section: Sod1 Maturation and Als Mutantsmentioning

confidence: 99%

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Wright

Antonyuk

Hasnain

2019

Quart. Rev. Biophys.

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“…Contrary to previous ideas, macromolecular crowding can destabilize proteins that are typically considered as stable when assessed at dilute concentrations (Miklos et al, 2011 ; Sarkar et al, 2012 ). SOD1 is no exception to this as evidence is emerging that even wild-type SOD1, in its metal-free and/or reduced form, is destabilized at a physiological temperature under crowded conditions (Bille et al, 2019 ; Takahashi et al, 2020 ). Indeed, in-cell nuclear magnetic resonance experiments of SOD1 have revealed that destabilization is common to both wild-type and ALS-associated mutants (Luchinat et al, 2014 ; Danielsson et al, 2015 ).…”

Section: In Vitro Models To Examine Proteostasis and Prion-lmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

McAlary

Chew

Lum

et al. 2020

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of the motor neurons that innervate muscle, resulting in gradual paralysis and culminating in the inability to breathe or swallow. This neuronal degeneration occurs in a spatiotemporal manner from a point of onset in the central nervous system (CNS), suggesting that there is a molecule that spreads from cell-to-cell. There is strong evidence that the onset and progression of ALS pathology is a consequence of protein misfolding and aggregation. In line with this, a hallmark pathology of ALS is protein deposition and inclusion formation within motor neurons and surrounding glia of the proteins TAR DNA-binding protein 43, superoxide dismutase-1, or fused in sarcoma. Collectively, the observed protein aggregation, in conjunction with the spatiotemporal spread of symptoms, strongly suggests a prion-like propagation of protein aggregation occurs in ALS. In this review, we discuss the role of protein aggregation in ALS concerning protein homeostasis (proteostasis) mechanisms and prion-like propagation. Furthermore, we examine the experimental models used to investigate these processes, including in vitro assays, cultured cells, invertebrate models, and murine models. Finally, we evaluate the therapeutics that may best prevent the onset or spread of pathology in ALS and discuss what lies on the horizon for treating this currently incurable disease.

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“…With >1000 residues, the systems have a computationally challenging size. However, systems of comparable size have been studied before with the same program 58 . Note also that it has been demonstrated that MC sampling can be a viable alternative to the more widely used molecular dynamics approach for dense protein systems 59 .…”

Section: Methodsmentioning

confidence: 99%

When a foreign gene meets its native counterpart: computational biophysics analysis of two PgiC loci in the grass Festuca ovina

Mohanty

Nilsson

et al. 2020

Sci Rep

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Duplicative horizontal gene transfer may bring two previously separated homologous genes together, which may raise questions about the interplay between the gene products. One such gene pair is the “native” PgiC1 and “foreign” PgiC2 in the perennial grass Festuca ovina. Both PgiC1 and PgiC2 encode cytosolic phosphoglucose isomerase, a dimeric enzyme whose proper binding is functionally essential. Here, we use biophysical simulations to explore the inter-monomer binding of the two homodimers and the heterodimer that can be produced by PgiC1 and PgiC2 in F. ovina. Using simulated native-state ensembles, we examine the structural properties and binding tightness of the dimers. In addition, we investigate their ability to withstand dissociation when pulled by a force. Our results suggest that the inter-monomer binding is tighter in the PgiC2 than the PgiC1 homodimer, which could explain the more frequent occurrence of the foreign PgiC2 homodimer in dry habitats. We further find that the PgiC1 and PgiC2 monomers are compatible with heterodimer formation; the computed binding tightness is comparable to that of the PgiC1 homodimer. Enhanced homodimer stability and capability of heterodimer formation with PgiC1 are properties of PgiC2 that may contribute to the retaining of the otherwise redundant PgiC2 gene.

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Stability and Local Unfolding of SOD1 in the Presence of Protein Crowders

Cited by 22 publications

References 60 publications

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

When a foreign gene meets its native counterpart: computational biophysics analysis of two PgiC loci in the grass Festuca ovina

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