Abstract
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.
Highlights
Protein aggregation/insolubility is characteristic of a broad spectrum of human diseases, in particular neurodegenerative/aging diseases[1,2], which include Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), spinocerebellar ataxias (SCA), and amyotrophic lateral sclerosis (ALS)
We discovered that the unstructured P56S, but not wild-type major sperm protein (MSP) domain, is able to insert into a membrane environment to become a helical structure[26], providing the underlying mechanism (Figure 1C) for the observation[22,24,25]
Formation of the helical conformations in membrane environments We first accessed the conformational properties in different environments by circular dichroism (CD) spectroscopy
Summary
Protein aggregation/insolubility is characteristic of a broad spectrum of human diseases, in particular neurodegenerative/aging diseases[1,2], which include Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), spinocerebellar ataxias (SCA), and amyotrophic lateral sclerosis (ALS). For the above mentioned diseases, aggregation/insolubility of specific proteins can be triggered by either genetic mutations (familiar) or environmental insults (sporadic), which strongly implies that a common mechanism may exist to initiate both familiar and sporadic forms of these clinically distinct diseases. The common mechanism to initiate these diseases still remains to be elucidated[1,7,8,9]. ALS is the most prevalent fatal motor neuron disease, yet its underlying mechanism still remains a mystery despite intense studies since the first description more than 130 years ago[10]. The MSP domain can be cleaved from its transmembrane anchor to serve as a ligand for the EphA4 receptor[1,14], which is the only-known ALS modifier[15].
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