E46K Parkinson’s-Linked Mutation Enhances C-Terminal-to-N-Terminal Contacts in α-Synuclein

Rospigliosi, Carla C.; McClendon, Sebastian; Schmid, Adrien W.; Ramlall, Trudy F.; Barré, Patrick; Lashuel, Hilal A.; Eliezer, David

doi:10.1016/j.jmb.2009.03.065

Cited by 90 publications

(110 citation statements)

References 56 publications

(84 reference statements)

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“…This observation of rigid structure being resistant to a high concentration of denaturant (6 M GdnHCl) is very unusual for proteins in general. However, this unique observation is consistent with the previous reports that E46K has a more compact structure with increased long range intramolecular interactions between its N and C termini (35,42,45). The higher resistance of Trp at position 3 of E46K to denaturation suggests that these intramolecular interactions are quite strong.…”

Section: Discussionsupporting

confidence: 92%

“…Several studies using various biophysical techniques including nuclear magnetic resonance (NMR) spectroscopy, time-resolved fluorescence energy transfer measurements, single molecule force spectroscopy, and molecular dynamics simulation have suggested that the PD-associated mutations A53T, E46K, and A30P alter the long range intramolecular interactions, structural compactness, and conformational equilibrium of the protein (41)(42)(43)(44)(45)(46)(47). However, the impact of these mutations on the structural properties of ␣-Syn is highly debated in the current literature (41,42). Despite all these studies, the structural basis for the increased oligomerization propensities of these PD-associated mutants is not yet clearly understood.…”

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confidence: 99%

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Familial Parkinson Disease-associated Mutations Alter the Site-specific Microenvironment and Dynamics of α-Synuclein

Sahay

Ghosh

Dwivedi

et al. 2015

Journal of Biological Chemistry

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Background: Aggregation of ␣-Syn is associated with PD pathogenesis. Results: Despite being natively unfolded, a site-specific structure exists in ␣-Syn that is significantly altered by familial PD-associated E46K, A53T, and A30P mutations. Conclusion: Altered site-specific structure of the PD-associated mutants may attribute to their different aggregation propensity. Significance: This study contributes to understanding the relationship between structure and aggregation of ␣-Syn.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Familial Parkinson Disease-associated Mutations Alter the Site-specific Microenvironment and Dynamics of α-Synuclein

Sahay

Ghosh

Dwivedi

et al. 2015

Journal of Biological Chemistry

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“…Overall, CD and NMR measurements indicated that the secondary structural properties of the wild-type and E46K mutant-type αS are similar to one another. 18,19,27,28 In contrast, SMF spectroscopy measurements indicated an number of β-sheet conformations upon E46K mutation of the wild-type αS. 25 Furthermore, E46K mutant-type αS is reported to convert to β-sheet conformations more readily than the wildtype αS.…”

Section: ■ Results and Discussionmentioning

confidence: 94%

Structures of the E46K Mutant-Type α-Synuclein Protein and Impact of E46K Mutation on the Structures of the Wild-Type α-Synuclein Protein

Wise-Scira

Dunn

Aloglu

et al. 2013

ACS Chem. Neurosci.

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The E46K genetic missense mutation of the wild-type α-synuclein protein was recently identified in a family of Spanish origin with hereditary Parkinson's disease. Detailed understanding of the structures of the monomeric E46K mutant-type α-synuclein protein as well as the impact of the E46K missense mutation on the conformations and free energy landscapes of the wild-type α-synuclein are required for gaining insights into the pathogenic mechanism of Parkinson's disease. In this study, we use extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to assess the secondary and tertiary structural properties as well as the conformational preferences of the monomeric wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment. We also present the residual secondary structure component conversion stabilities with dynamics using a theoretical strategy, which we most recently developed. To the best of our knowledge, this study presents the first detailed comparison of the structural and thermodynamic properties of the wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment at the atomic level with dynamics. We find that the E46K mutation results not only in local but also in long-range changes in the structural properties of the wild-type α-synuclein protein. The mutation site shows a significant decrease in helical content as well as a large increase in β-sheet structure formation upon E46K mutation. In addition, the β-sheet content of the C-terminal region increases significantly in the E46K mutant-type αS in comparison to the wild-type αS. Our theoretical strategy developed to assess the thermodynamic preference of secondary structure transitions indicates that this shift in secondary structure is the result of a decrease in the thermodynamic preference of turn to helix conversions while the coil to β-sheet preference increases for these residues. Long-range intramolecular protein interactions of the C-terminal with the N-terminal and NAC regions increase upon E46K mutation, resulting in more compact structures for the E46K mutant-type rather than wild-type αS. However, the E46K mutant-type αS structures are less stable than the wild-type αS. Overall, our results show that the E46K mutant-type αS has a higher propensity to aggregate than the wild-type αS and that the N-terminal and C-terminal regions are reactive toward fibrillization and aggregation upon E46K mutation and we explain the associated reasons based on the structural properties herein. Small molecules or drugs that can block the specific residues forming abundant β-sheet structure, which we report here, might help to reduce the reactivity of these intrinsically disordered fibrillogenic proteins toward aggregation and their toxicity.

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“…With respect to the effects of PD-linked mutations on the free state of ␣S, some reports have suggested that these muta- tions may alter long range contacts between the C-terminal tail and the N-terminal lipid-binding domain of the protein (58,59). The experiments we describe here monitor the compactness of the lipid-binding domain of the protein, and within the accuracy of our results, no significant differences were found in the spatial extent of this domain of the WT and three PD-linked mutations.…”

Section: Discussionmentioning

confidence: 99%

The Lipid-binding Domain of Wild Type and Mutant α-Synuclein

Georgieva

Ramlall

Borbat

et al. 2010

Journal of Biological Chemistry

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␣-Synuclein (␣S) is linked to Parkinson disease through its deposition in an amyloid fibril form within Lewy Body deposits, and by the existence of three ␣S point mutations that lead to early onset autosomal dominant Parkinsonism. The normal function of ␣S is thought to be linked to the ability of the protein to bind to the surface of synaptic vesicles. Upon binding to vesicles, ␣S undergoes a structural reorganization from a dynamic and disordered ensemble to a conformation consisting of a long extended helix. In the presence of small spheroidal detergent micelles, however, this extended helix conformation can convert into a broken helix state, in which a region near the middle of the helix unwinds to form a linker between the two resulting separated helices. Membrane-bound conformations of ␣S likely mediate the function of the protein, but may also play a role in the aggregation and toxicity of the protein. Here we have undertaken a study of the effects of the three known PD-linked mutations on the detergent-and membrane-bound conformations of ␣S, as well as factors that govern the transition of the protein between the extended helix and broken helix states. Using pulsed dipolar ESR measurements of distances up to 8.7 nm, we show that all three PD-linked ␣S mutants retain the ability to transition from the broken helix to the extended helix conformation. In addition, we find that the ratio of protein to detergent, rather than just the absolute detergent concentration, determines whether the protein adopts the broken or extended helix conformation.Since its initial discovery as a protein enriched in the electric organ of the Pacific electric ray, Torpedo californica (1), the protein ␣-synuclein has been progressively associated with a role in neurodegeneration in humans, starting with its identification as the precursor protein of a non-amyloid-␤ peptide component of amyloid plaques (the so-called NAC peptide) (2) and culminating in its discovery as the first gene product to be linked to familial Parkinson disease (3) and its contemporaneous identification as the primary component of the fibrillary aggregates found in the hallmark Lewy body deposits associated with Parkinson (4).Subsequently, a great deal of effort has been made to clarify and understand the mechanisms by which ␣S causes neuronal degeneration, as well as to understand the normal functional roles of ␣S and how these are related to its role in disease (5, 6). Although aggregation of ␣S remains a key focus in these efforts, it remains possible that other, or additional, effects beyond the presence of various aggregated species of ␣S may be involved in the etiology of synuclein-associated PD. A key piece of the puzzle that remains unanswered is which of the various forms of ␣S that have been observed in vitro are involved in mediating the toxicity of the protein in vivo. In particular, although ␣S is highly disordered when isolated in solution in vitro (7-9) it is not clear to what extent this intrinsically disordered state is populated in vivo. Be...

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E46K Parkinson’s-Linked Mutation Enhances C-Terminal-to-N-Terminal Contacts in α-Synuclein

Cited by 90 publications

References 56 publications

Familial Parkinson Disease-associated Mutations Alter the Site-specific Microenvironment and Dynamics of α-Synuclein

Familial Parkinson Disease-associated Mutations Alter the Site-specific Microenvironment and Dynamics of α-Synuclein

Structures of the E46K Mutant-Type α-Synuclein Protein and Impact of E46K Mutation on the Structures of the Wild-Type α-Synuclein Protein

The Lipid-binding Domain of Wild Type and Mutant α-Synuclein

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