Login Register Cart 0
Generic placeholder image

Current Biotechnology

Editor-in-Chief

ISSN (Print): 2211-5501
ISSN (Online): 2211-551X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Conformational Dynamics of Post-Translational-Modified α-Synuclein (pY39 and pS87) and its Interaction with Lipid Membrane

Author(s): Dorothy Das and Venkata Satish Kumar Mattaparthi*

Volume 13, Issue 2, 2024

Published on: 04 June, 2024

Page: [119 - 130] Pages: 12

DOI: 10.2174/0122115501310995240522064640

Price: $65

Open Access Journals Promotions 2
conference banner
Abstract

Background: The biological function of α-Synuclein (α-Syn), which includes controlling synaptic vesicles, is regulated by phosphorylation at the Tyrosine 39 (pY39) residue. This function can be important for both normal and aberrant functions, and it relies on the interaction of α-Syn with the lipid membrane. pY39 α-Syn is found to form morphologically distinct fibrils relative to wild-type (WT) α-Syn and shows less affinity to negatively charged vesicles. Also, the phosphorylation at position Serine 87 (pS87) is increased in synucleinopathies, which inhibits α- Syn oligomerization and affects the interaction between α-Syn and the membrane.

Objective: This work aimed to study the effects of post-translation modifications of α-Syn (pY39 and pS87) using all-atom Molecular Dynamics (MD) simulation.

Method: In this computational study, we used all-atom MD simulations to investigate the effects of phosphorylation (pY39 and pS87) on protein-membrane interaction. The MD trajectories obtained were analyzed, and secondary structural content was calculated using YASARA software to perform a salt-bridge interaction study. Also, Principal component analysis was performed to analyze the secondary minima and global minima of the phosphorylated proteins.

Results: From the MD study, we observed that phosphorylation at the Tyr 39 position in α-Syn has a marked effect on its interaction with the lipid membrane. The conformational snapshots of α-Syn obtained showed a high degree of fluctuations in the N-terminal region that disrupts the helix- 2 binding region. The secondary structures of pS87 α-Syn were found to be retained and influence the NAC region to immerse into the membrane while inhibiting the potential to interact with other neighbouring molecules. Moreover, it was observed that in the case of pY39 α-Syn as opposed to pS87 α-Syn, there were larger energy disparities between the local and global minima of the overall structure.

Conclusion: Therefore, disruption of the helix-2 binding region may affect the binding to the lipid membrane and take over interaction with other proteins or vesicles. In the case of pS87 α-Syn, the structure showed higher stability, but the NAC domain was found to emerge out of the membrane.

Keywords: Membrane dynamics, phosphorylated α-Syn, protein aggregation, molecular dynamics, α-Synuclein, parkinson’s disease.

« Previous Next »
Graphical Abstract

[1]
Barrett PJ, Timothy Greenamyre J. Post-translational modification of α-synuclein in Parkinson's disease. Brain Res 2015; 1628(Pt B): 247-53.
[http://dx.doi.org/10.1016/j.brainres.2015.06.002] [PMID: 26080075]
[2]
Schmid AW, Fauvet B, Moniatte M, Lashuel HA. α-synuclein post-translational modifications as potential biomarkers for Parkinson disease and other synucleinopathies. Mol Cell Proteomics 2013; 12(12): 3543-58.
[http://dx.doi.org/10.1074/mcp.R113.032730] [PMID: 23966418]
[3]
Reeve A, Simcox E, Turnbull D. Ageing and Parkinson’s disease: Why is advancing age the biggest risk factor? Ageing Res Rev 2014; 14(100): 19-30.
[http://dx.doi.org/10.1016/j.arr.2014.01.004] [PMID: 24503004]
[4]
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 1998; 95(11): 6469-73.
[http://dx.doi.org/10.1073/pnas.95.11.6469] [PMID: 9600990]
[5]
Fujiwara H, Hasegawa M, Dohmae N, et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 2002; 4(2): 160-4.
[http://dx.doi.org/10.1038/ncb748] [PMID: 11813001]
[6]
Anderson JP, Walker DE, Goldstein JM, et al. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 2006; 281(40): 29739-52.
[http://dx.doi.org/10.1074/jbc.M600933200] [PMID: 16847063]
[7]
Oueslati A, Fournier M, Lashuel HA. Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein. Prog Brain Res 2010; 183: 115-45.
[http://dx.doi.org/10.1016/S0079-6123(10)83007-9] [PMID: 20696318]
[8]
Paleologou KE, Oueslati A, Shakked G, et al. Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci 2010; 30(9): 3184-98.
[http://dx.doi.org/10.1523/JNEUROSCI.5922-09.2010] [PMID: 20203178]
[9]
Okochi M, Walter J, Koyama A, et al. Constitutive phosphorylation of the Parkinson’s disease associated alpha-synuclein. J Biol Chem 2000; 275(1): 390-7.
[http://dx.doi.org/10.1074/jbc.275.1.390] [PMID: 10617630]
[10]
Kim EJ, Sung JY, Lee HJ, et al. Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation. J Biol Chem 2006; 281(44): 33250-7.
[http://dx.doi.org/10.1074/jbc.M606147200] [PMID: 16959772]
[11]
Fournier M, Vitte J, Garrigue J, et al. Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy. PLoS One 2009; 4(8): e6629.
[http://dx.doi.org/10.1371/journal.pone.0006629] [PMID: 19680561]
[12]
Uéda K, Fukushima H, Masliah E, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 1993; 90(23): 11282-6.
[http://dx.doi.org/10.1073/pnas.90.23.11282] [PMID: 8248242]
[13]
El-Agnaf OMA, Jakes R, Curran MD, et al. Aggregates from mutant and wild-type α-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β-sheet and amyloid-like filaments. FEBS Lett 1998; 440(1-2): 71-5.
[http://dx.doi.org/10.1016/S0014-5793(98)01418-5] [PMID: 9862428]
[14]
Giasson BI, Murray IVJ, Trojanowski JQ, Lee VMY. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J Biol Chem 2001; 276(4): 2380-6.
[http://dx.doi.org/10.1074/jbc.M008919200] [PMID: 11060312]
[15]
Luk KC, Song C, O’Brien P, et al. Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci USA 2009; 106(47): 20051-6.
[http://dx.doi.org/10.1073/pnas.0908005106] [PMID: 19892735]
[16]
Waxman EA, Mazzulli JR, Giasson BI. Characterization of hydrophobic residue requirements for alpha-synuclein fibrillization. Biochemistry 2009; 48(40): 9427-36.
[http://dx.doi.org/10.1021/bi900539p] [PMID: 19722699]
[17]
Sonustun B, Altay MF, Strand C, et al. Pathological relevance of post-translationally modified alpha-synuclein (pSer87, pSer129, nTyr39) in idiopathic parkinson’s disease and multiple system atrophy. Cells 2022; 11(5): 906.
[http://dx.doi.org/10.3390/cells11050906] [PMID: 35269528]
[18]
Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of α-synuclein: From structure and toxicity to therapeutic target. Nat Rev Neurosci 2013; 14(1): 38-48.
[http://dx.doi.org/10.1038/nrn3406] [PMID: 23254192]
[19]
Sanjeev A, Mattaparthi VSK. Investigation on the molecular interactions stabilizing the structure of α-synuclein fibril: An in silico study. Cent Nerv Syst Agents Med Chem 2017; 17(3): 209-18.
[http://dx.doi.org/10.2174/1871524917666170427152849] [PMID: 28460628]
[20]
Zhao K, Lim YJ, Liu Z, et al. Parkinson’s disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM. Proc Natl Acad Sci USA 2020; 117(33): 20305-15.
[http://dx.doi.org/10.1073/pnas.1922741117] [PMID: 32737160]
[21]
Berman HM, Battistuz T, Bhat TN, et al. The protein data bank. Acta Crystallogr D Biol Crystallogr 2002; 58(6): 899-907.
[http://dx.doi.org/10.1107/S0907444902003451] [PMID: 12037327]
[22]
Case DA, Ben-Shalom IY, Brozell SR, et al. Amber 2018. San Francisco: University of California 2018.
[23]
Jo S, Kim T, Iyer VG, Im W. CHARMM-GUI: A web-based graphical user interface for CHARMM. J Comput Chem 2008; 29(11): 1859-65.
[http://dx.doi.org/10.1002/jcc.20945] [PMID: 18351591]
[24]
Fusco G, Pape T, Stephens AD, et al. Structural basis of synaptic vesicle assembly promoted by α-synuclein. Nat Commun 2016; 7(1): 12563.
[http://dx.doi.org/10.1038/ncomms12563] [PMID: 27640673]
[25]
Das D, Mattaparthi VSK. Conformational dynamics of A30G α-synuclein that causes familial Parkinson disease. J Biomol Struct Dyn 2023; 41(24): 14702-14.
[http://dx.doi.org/10.1080/07391102.2023.2193997] [PMID: 36961209]
[26]
Roe DR, Cheatham TE III. PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput 2013; 9(7): 3084-95.
[http://dx.doi.org/10.1021/ct400341p] [PMID: 26583988]
[27]
Kabsch W, Sander C. Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 1983; 22(12): 2577-637.
[http://dx.doi.org/10.1002/bip.360221211] [PMID: 6667333]
[28]
Land H, Humble MS. Yasara: A tool to obtain structural guidance in biocatalytic investigations. Methods Mol Biol 2018; 1685: 43-67.
[http://dx.doi.org/10.1007/978-1-4939-7366-8_4] [PMID: 29086303]
[29]
Liu Y, Wan Y, Zhu J, et al. Theoretical study on zearalenol compounds binding with wild type zearalenone hydrolase and V153H mutant. Int J Mol Sci 2018; 19(9): 2808.
[http://dx.doi.org/10.3390/ijms19092808] [PMID: 30231501]
[30]
Sarakatsannis JN, Duan Y. Statistical characterization of salt bridges in proteins. Proteins 2005; 60(4): 732-9.
[http://dx.doi.org/10.1002/prot.20549] [PMID: 16021620]
[31]
Pathak C, Vaidya FU, Waghela BN, et al. Insights of endocytosis signaling in health and disease. Int J Mol Sci 2023; 24(3): 2971.
[http://dx.doi.org/10.3390/ijms24032971] [PMID: 36769293]
[32]
Das D, Bharadwaz P, Mattaparthi VSK. Computational investigation on the effect of the peptidomimetic inhibitors (NPT100-18A and NPT200-11) on the α-synuclein and lipid membrane interactions. J Biomol Struct Dyn 2023; 28: 1-12.
[http://dx.doi.org/10.1080/07391102.2023.2262599] [PMID: 37768058]
[33]
Sanjeev A, Mattaparthi VSK. Computational investigation on the effects of H50Q and G51D mutations on the α-Synuclein aggregation propensity. J Biomol Struct Dyn 2018; 36(9): 2224-36.
[http://dx.doi.org/10.1080/07391102.2017.1347060] [PMID: 28650719]
[34]
Le S, Yu M, Yan J. Phosphorylation reduces the mechanical stability of the α-catenin/ β-catenin complex. Angew Chem Int Ed 2019; 58(51): 18663-9.
[http://dx.doi.org/10.1002/anie.201911383] [PMID: 31625226]
[35]
Huang W, Liu J, Le S, Yao M, Shi Y, Yan J. In situ single molecule investigations of the impacts of biochemical perturbations on conformational intermediates of monomeric α-synuclein. APL Bioeng 2024; 8(1): 016114.
[http://dx.doi.org/10.1063/5.0188714] [PMID: 38435467]
[36]
Spassov DS, Atanasova M, Doytchinova I. A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors. Front Mol Biosci 2023; 9: 1066029.
[http://dx.doi.org/10.3389/fmolb.2022.1066029] [PMID: 36703920]

Rights & Permissions Print Cite
Article Metrics
18
2
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy