Novel splice variants of the amyotrophic lateral sclerosis-associated gene VAPB expressed in human tissues

Nachreiner, Thomas; Esser, Marc; Tenten, Verena; Troost, Dirk; Weis, Joachim; Krüttgen, Alex

doi:10.1016/j.bbrc.2010.03.055

Cited by 19 publications

(19 citation statements)

References 21 publications

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“…Moreover, it also appears challenging to detect the initial interaction between these cytosolic aggregated proteins with membranes at the early stage because most of them may not cause significant morphological changes in cells. Only upon proteasomal inhibition, a condition commonly found in neurodegenerative diseases 86 , do aggregated proteins such as VAPB3, an insoluble splicing variant of VAPB without an ER-anchored region, accumulate and thus have opportunities to access and attack membranes, and thus lead to sporadic diseases. Indeed, an increased expression of the wild-type α-synuclein due to gene duplication and triplication is required to initiate Parkinson’s disease 61, 63 .…”

Section: Discussionmentioning

confidence: 99%

Resolving the paradox for protein aggregation diseases: NMR structure and dynamics of the membrane-embedded P56S-MSP causing ALS imply a common mechanism for aggregation-prone proteins to attack membranes

et al. 2014

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Paradoxically, aggregation of specific proteins is characteristic of many human diseases and aging, yet aggregates have increasingly been found to be unnecessary for initiating pathogenesis. Here we determined the NMR topology and dynamics of a helical mutant in a membrane environment transformed from the 125-residue cytosolic all-β MSP domain of vesicle-associated membrane protein-associated protein B (VAPB) by the ALS-causing P56S mutation. Despite its low hydrophobicity, the P56S major sperm protein (MSP) domain becomes largely embedded in the membrane environment with high backbone rigidity. Furthermore it is composed of five helices with amphiphilicity comparable to those of the partly-soluble membrane toxin mellitin and α-synuclein causing Parkinson's disease. Consequently, the mechanism underlying this chameleon transformation becomes clear: by disrupting the specific tertiary interaction network stabilizing the native all-β MSP fold to release previously-locked amphiphilic segments, the P56S mutation acts to convert the classic MSP fold into a membrane-active protein that is fundamentally indistinguishable from mellitin and α-synuclein which are disordered in aqueous solution but spontaneously partition into membrane interfaces driven by hydrogen-bond energetics gained from forming α-helix in the membrane environments. As segments with high amphiphilicity exist in all proteins, our study successfully resolves the paradox by deciphering that the proteins with a higher tendency to aggregate have a stronger potential to partition into membranes through the same mechanism as α-synuclein to initially attack membranes to trigger pathogenesis without needing aggregates. This might represent the common first step for various kinds of aggregated proteins to trigger familiar, sporadic and aging diseases. Therefore the homeostasis of aggregated proteins in vivo is the central factor responsible for a variety of human diseases including aging. The number and degree of the membrane attacks by aggregated proteins may act as an endogenous clock to count down the aging process. Consequently, a key approach to fight against them is to develop strategies and agents to maintain or even enhance the functions of the degradation machineries.

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Section: Discussionmentioning

confidence: 99%

Resolving the paradox for protein aggregation diseases: NMR structure and dynamics of the membrane-embedded P56S-MSP causing ALS imply a common mechanism for aggregation-prone proteins to attack membranes

et al. 2014

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“…These sequences may escape detection by bioinformatics tools for identifying IUPs as their sequences show no detectable difference from those that adopt well-folded structures. For example, VAPB-3, a splicing variant of VAPB, is both insoluble and unstructured 84, 85 .…”

Section: Intrinsically Insoluble Proteinsmentioning

confidence: 99%

Why do proteins aggregate? “Intrinsically insoluble proteins” and “dark mediators” revealed by studies on “insoluble proteins” solubilized in pure water

Song

2013

F1000Res

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In 2008, I reviewed and proposed a model for our discovery in 2005 that unrefoldable and insoluble proteins could in fact be solubilized in unsalted water. Since then, this discovery has offered us and other groups a powerful tool to characterize insoluble proteins, and we have further addressed several fundamental and disease-relevant issues associated with this discovery. Here I review these results, which are conceptualized into several novel scenarios. 1) Unlike 'misfolded proteins', which still retain the capacity to fold into well-defined structures but are misled to 'off-pathway' aggregation, unrefoldable and insoluble proteins completely lack this ability and will unavoidably aggregate in vivo with ~150 mM ions, thus designated as 'intrinsically insoluble proteins (IIPs)' here. IIPs may largely account for the 'wastefully synthesized' DRiPs identified in human cells. 2) The fact that IIPs including membrane proteins are all soluble in unsalted water, but get aggregated upon being exposed to ions, logically suggests that ions existing in the background play a central role in mediating protein aggregation, thus acting as 'dark mediators'. Our study with 14 salts confirms that IIPs lack the capacity to fold into any well-defined structures. We uncover that salts modulate protein dynamics and anions bind proteins with high selectivity and affinity, which is surprisingly masked by pre-existing ions. Accordingly, I modified my previous model. 3) Insoluble proteins interact with lipids to different degrees. Remarkably, an ALS-causing P56S mutation transforms the β-sandwich MSP domain into a helical integral membrane protein. Consequently, the number of membrane-interacting proteins might be much larger than currently recognized. To attack biological membranes may represent a common mechanism by which aggregated proteins initiate human diseases. 4) Our discovery also implies a solution to the 'chicken-and-egg paradox' for the origin of primitive membranes embedded with integral membrane proteins, if proteins originally emerged in unsalted prebiotic media.

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“…Furthermore, we showed that the splicing variant of VAPB was also insoluble in buffers and highly disordered in the salt-minimized water (Qin et al 2013a). Remarkably, this splicing variant has been found only to become accumulated upon proteasomal inhibition, a condition commonly found in neurodegenerative diseases (Nachreiner et al 2010). …”

Section: Aggregation and Self-assembly Into Liquid Droplets And Fibrimentioning

confidence: 99%

“…Additionally, the eukaryotic, particularly human genomes appear to contain a large amount of IIPs, most, if not all, of which are also capable of interacting with membranes. Consequently, they might also act to initiate diseases and aging when their expression is increased, and/or degradation is reduced under some pathological, aging and/or environmental conditions (Nachreiner et al 2010;Qin et al 2013b).…”

Section: Transformation From Cytosolic Proteins Into Membrane-interacmentioning

confidence: 99%

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

Song

2017

Biophys Rev

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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.

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Novel splice variants of the amyotrophic lateral sclerosis-associated gene VAPB expressed in human tissues

Cited by 19 publications

References 21 publications

Resolving the paradox for protein aggregation diseases: NMR structure and dynamics of the membrane-embedded P56S-MSP causing ALS imply a common mechanism for aggregation-prone proteins to attack membranes

Resolving the paradox for protein aggregation diseases: NMR structure and dynamics of the membrane-embedded P56S-MSP causing ALS imply a common mechanism for aggregation-prone proteins to attack membranes

Why do proteins aggregate? “Intrinsically insoluble proteins” and “dark mediators” revealed by studies on “insoluble proteins” solubilized in pure water

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

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