Exploring the accessible conformations of N‐terminal acetylated α‐synuclein

Moriarty, Gina M.; Janowska, Maria K.; Kang, Lijuan; Baum, Jean

doi:10.1016/j.febslet.2013.02.049

Cited by 32 publications

(26 citation statements)

References 169 publications

(282 reference statements)

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“…␣-Synuclein (␣S), 5 the primary protein component of intracytoplasmic inclusions known as Lewy bodies (LB) in Parkinson's disease (PD), is a 140-residue, predominantly monomeric, intrinsically disordered protein (IDP) (1)(2)(3)(4)(5)(6). It is abundant in the cytosol but present in many organelles (7,8).…”

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confidence: 99%

A pH-dependent switch promotes β-synuclein fibril formation via glutamate residues

Moriarty

Olson

Atieh

et al. 2017

Journal of Biological Chemistry

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Edited by Wolfgang Peti ␣-Synuclein (␣S) is the primary protein associated with Parkinson's disease, and it undergoes aggregation from its intrinsically disordered monomeric form to a cross-␤ fibrillar form. The closely related homolog ␤-synuclein (␤S) is essentially fibril-resistant under cytoplasmic physiological conditions. Toxic gain-of-function by ␤S has been linked to dysfunction, but the aggregation behavior of ␤S under altered pH is not wellunderstood. In this work, we compare fibril formation of ␣S and ␤S at pH 7.3 and mildly acidic pH 5.8, and we demonstrate that pH serves as an on/off switch for ␤S fibrillation. Using ␣S/␤S domain-swapped chimera constructs and single residue substitutions in ␤S, we localized the switch to acidic residues in the N-terminal and non-amyloid component domains of ␤S. Computational models of ␤S fibril structures indicate that key glutamate residues (Glu-31 and Glu-61) in these domains may be sites of pH-sensitive interactions, and variants E31A and E61A show dramatically altered pH sensitivity for fibril formation supporting the importance of these charged side chains in fibril formation of ␤S. Our results demonstrate that relatively small changes in pH, which occur frequently in the cytoplasm and in secretory pathways, may induce the formation of ␤S fibrils and suggest a complex role for ␤S in synuclein cellular homeostasis and Parkinson's disease. ␣-Synuclein (␣S),5 the primary protein component of intracytoplasmic inclusions known as Lewy bodies (LB) in Parkinson's disease (PD), is a 140-residue, predominantly monomeric, intrinsically disordered protein (IDP) (1-6). It is abundant in the cytosol but present in many organelles (7,8). The monomers of ␣S can aggregate to soluble oligomers as well as insoluble oligomers and fibrils, which are considered to be associated with the pathogenesis of PD (9). A closely related family member, ␤-synuclein (␤S) that co-localizes with ␣S, has ϳ60% sequence identity with ␣S but has not been detected in LBs of PD patients (10, 11). Instead, it has been proposed that ␤S may delay ␣S fibril formation and ameliorate ␣S toxicity in vivo by inhibiting ␣S aggregation (12-14). Furthermore, despite the high sequence similarity, ␤S itself does not form fibrils in vitro at cytoplasmic pH without facilitating agents (15). However, recent reports highlight a role for a possible toxic gain-of-function of ␤S in two different model systems (16,17), and ␤S is a component of vesicle-like lesions in the hippocampus, whose formation accompanies dementia in PD (18). In addition, two ␤S mutations, V70M and P123H, were found in sporadic and familial dementia with LBs and have been suggested to be involved in lysosomal pathology (19 -21). There is an emerging role for ␤S in the pathophysiology of PD, but the molecular determinants of this role remain poorly studied.Understanding the complex relationship of synucleins with neurodegeneration requires consideration of their structures and functions in diverse subcellular environments, beyond the cytoplasm. Altho...

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confidence: 99%

A pH-dependent switch promotes β-synuclein fibril formation via glutamate residues

Moriarty

Olson

Atieh

et al. 2017

Journal of Biological Chemistry

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“…[7,9] Furthermore, in buffered solution α-synuclein exists as an intrinsically disordered monomer, [10] with its conformational heterogeneity extending into higher oligomeric states. [35] For SPR experiment homogenous sample is a prerequisite for satisfactory measurement. Nevertheless, monomeric conformation highly prevails even at the higher α-synuclein concentration used here (i.e.…”

Section: Resultsmentioning

confidence: 99%

Interaction of α-Synuclein with Negatively Charged Lipid Membranes Monitored by Surface Plasmon Resonance

Pirc¹,

Hodnik²,

Ulrih³

et al. 2016

Croat. Chem. Acta

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Aggregation of presynaptic protein α-synuclein is implicated in the development of Parkinson's disease. Interaction of α-synuclein with lipid membranes appears to be critical for its physiological and pathological roles. Anionic lipids trigger conformational transition of α-synuclein from its natively disordered into an α-helical structure. Here we used surface plasmon resonance (SPR) to determine the affinities of α-synuclein for the small unilamellar vesicles composed of anionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS) or 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG) and neutral 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids. α-Synuclein bound in a concentration dependent manner to equimolar mixtures of POPC/POPS and POPC/DPPG vesicles. The affinity of α-synuclein for POPC/POPS was ~3 -fold higher than for POPC/DPPG. These results indicate that headgroup charge is not the only factor contributing to α-synuclein-membrane association.

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“…Structurally, human α-synuclein is a typical IDP (Uversky et al 2001a ;Uversky 2003aUversky , 2007Uversky , 2008aWu et al 2008 ;Uversky and Eliezer 2009 ;Wu and Baum 2010 ;Breydo et al 2012 ;Dikiy and Eliezer 2012 ;Binolfi et al 2012 ;Fauvet et al 2012a , b ;Moriarty et al 2013 ). In the presence of several divalent and trivalent metal ions (Uversky et al 2001b(Uversky et al , 2002aBreydo and Uversky 2011 ) and/or several common pesticides (Uversky 2004 ;Uversky et al 2001cUversky et al , 2002aSilva et al 2013 ), α-synuclein can adopt a partially folded conformation, which is critical for fi brillation, suggesting that these metals and pesticides can serve as potential promoters of Parkinson's disease.…”

Section: Aggregation Of α-Synuclein In Various Alcoholsmentioning

confidence: 99%

Protein Misfolding in Lipid-Mimetic Environments

Uversky

2015

Advances in Experimental Medicine and Biology

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Among various cellular factors contributing to protein misfolding and subsequent aggregation, membranes occupy a special position due to the two-way relations between the aggregating proteins and cell membranes. On one hand, the unstable, toxic pre-fibrillar aggregates may interact with cell membranes, impairing their functions, altering ion distribution across the membranes, and possibly forming non-specific membrane pores. On the other hand, membranes, too, can modify structures of many proteins and affect the misfolding and aggregation of amyloidogenic proteins. The effects of membranes on protein structure and aggregation can be described in terms of the "membrane field" that takes into account both the negative electrostatic potential of the membrane surface and the local decrease in the dielectric constant. Water-alcohol (or other organic solvent) mixtures at moderately low pH are used as model systems to study the joint action of the local decrease of pH and dielectric constant near the membrane surface on the structure and aggregation of proteins. This chapter describes general mechanisms of structural changes of proteins in such model environments and provides examples of various proteins aggregating in the "membrane field" or in lipid-mimetic environments.

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Exploring the accessible conformations of N‐terminal acetylated α‐synuclein

Cited by 32 publications

References 169 publications

A pH-dependent switch promotes β-synuclein fibril formation via glutamate residues

A pH-dependent switch promotes β-synuclein fibril formation via glutamate residues

Interaction of α-Synuclein with Negatively Charged Lipid Membranes Monitored by Surface Plasmon Resonance

Protein Misfolding in Lipid-Mimetic Environments

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