Chinese Journal of Magnetic Resonance >
Inhibition of α-Synuclein Aggregation by the Interaction Between Protein Disulfide Isomerase and α-Synuclein
Received date: 2022-01-28
Online published: 2022-03-10
Abnormally misfolded and aggregated α-synuclein (αsyn) is the hallmark of Parkinson's disease (PD). Molecular chaperone protein disulfide isomerase (PDI) has been shown to interact with αsyn and inhibit its aggregation in vitro, but the mechanism for the recognition of αsyn by PDI is not yet clear. Herein, we used nuclear magnetic resonance (NMR) spectroscopy to identify that human PDI b'xa' bound with the N-terminal domain of αsyn, and thioflavin T (ThT) fluorescence assay revealed that b'xa' domain of PDI significantly inhibited αsyn aggregation. Furthermore, by using NMR titration, we observed that PDI bound to αsyn mainly through its hydrophobic cavity of the b' domain. Based on these findings, a docking model of PDI binding with αsyn was established and a possible mechanism of how PDI inhibits αsyn aggregation was proposed. Our work provides experimental evidences for understanding the inhibitory role of PDI in αsyn aggregation.
Yun-shan PEI , Cai ZHANG , Xiao-li LIU , Kai CHENG , Ze-ting ZHANG , Cong-gang LI . Inhibition of α-Synuclein Aggregation by the Interaction Between Protein Disulfide Isomerase and α-Synuclein[J]. Chinese Journal of Magnetic Resonance, 2022 , 39(4) : 381 -392 . DOI: 10.11938/cjmr20222974
| 1 | THEILLET F X, BINOLFI A, BEKEI B, et al Structural disorder of monomeric α-synuclein persists in mammalian cells[J]. Nature, 2016, 530 (7588): 45- 50. |
| 2 | WEINREB P H, ZHEN W, POON A W, et al NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded[J]. Biochemistry, 1996, 35 (43): 13709- 13715. |
| 3 | IADANZA M G, JACKSON M P, HEWITT E W, et al A new era for understanding amyloid structures and disease[J]. Nat Rev Mol Cell Biol, 2018, 19 (12): 755- 773. |
| 4 | LIU C W, GIASSON B I, LEWIS K A, et al A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation - Implications for pathogenesis of Parkinson disease[J]. J Biol Chem, 2005, 280 (24): 22670- 22678. |
| 5 | DETTMER U, SELKOE D, BARTELS T New insights into cellular α-synuclein homeostasis in health and disease[J]. Curr Opin Neurobiol, 2016, 36, 15- 22. |
| 6 | SPILLANTINI M G, SCHMIDT M L, LEE V M Y, et al α-Synuclein in Lewy bodies[J]. Nature, 1997, 388 (6645): 839- 840. |
| 7 | LAUTENSCHL GER J, KAMINSKI C F, KAMINSKI SCHIERLE G S α-synuclein – regulator of exocytosis, endocytosis, or both?[J]. Trends in Cell Biol, 2017, 27 (7): 468- 479. |
| 8 | MAHUL-MELLIER A L, BURTSCHER J, MAHARJAN N, et al The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration[J]. Proc Natl Acad Sci U S A, 2020, 117 (9): 4971- 4982. |
| 9 | SHAHMORADIAN S H, LEWIS A J, GENOUD C, et al Lewy pathology in Parkinson's disease consists of crowded organelles and lipid membranes[J]. Nat Neurosci, 2019, 22 (7): 1099- 1109. |
| 10 | BARTELS T, AHLSTROM L S, LEFTIN A, et al The N-terminus of the intrinsically disordered protein α-synuclein triggers membrane binding and helix folding[J]. Biophys J, 2010, 99 (7): 2116- 2124. |
| 11 | BURMANN B M, GEREZ J A, MATE?KO-BURMANN I, et al Regulation of α-synuclein by chaperones in mammalian cells[J]. Nature, 2020, 577 (7788): 127- 132. |
| 12 | GRUSCHUS J M, YAP T L, PISTOLESI S, et al NMR structure of calmodulin complexed to an N-terminally acetylated α-synuclein peptide[J]. Biochemistry, 2013, 52 (20): 3436- 3445. |
| 13 | GIASSON B I, MURRAY I V, TROJANOWSKI J Q, et al A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly[J]. J Biol Chem, 2001, 276 (4): 2380- 2386. |
| 14 | BINOLFI A, RASIA R M, BERTONCINI C W, et al Interaction of alpha-synuclein with divalent metal ions reveals key differences: A link between structure, binding specificity and fibrillation enhancement[J]. J Am Chem Soc, 2006, 128 (30): 9893- 9901. |
| 15 | NIELSEN M S, VORUM H, LINDERSSON E, et al Ca2+ binding to alpha-synuclein regulates ligand binding and oligomerization[J]. J Biol Chem, 2001, 276 (25): 22680- 22684. |
| 16 | BINOLFI A, RASIA R M, BERTONCINI C W, et al Interaction of alpha-synuclein with divalent metal ions reveals key differences: a link between structure, binding specificity and fibrillation enhancement[J]. J Am Chem Soc, 2006, 128 (30): 9893- 9901. |
| 17 | SERRANO A, QIAO X, MATOS J O, et al Reversal of alpha-synuclein fibrillization by protein disulfide isomerase[J]. Front Cell Dev Biol, 2020, 8, 726. |
| 18 | DEDMON M M, CHRISTODOULOU J, WILSON M R, et al Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species[J]. J Biol Chem, 2005, 280 (15): 14733- 14740. |
| 19 | DIMANT H, EBRAHIMI-FAKHARI D, MCLEAN P J Molecular chaperones and co-chaperones in Parkinson disease[J]. Neuroscientist, 2012, 18 (6): 589- 601. |
| 20 | GAO X, CARRONI M, NUSSBAUM-KRAMMER C, et al Human Hsp70 disaggregase reverses Parkinson's-linked α-synuclein amyloid fibrils[J]. Mol Cell, 2015, 59 (5): 781- 793. |
| 21 | PEMBERTON S, MADIONA K, PIERI L, et al Hsc70 protein interaction with soluble and fibrillar alpha-synuclein[J]. J Biol Chem, 2011, 286 (40): 34690- 34699. |
| 22 | RANJAN P, KUMAR A The involvement of His50 during protein disulfide isomerase binding is essential for inhibiting α-Syn fibril formation[J]. Biochemistry, 2016, 55 (19): 2677- 2680. |
| 23 | UEHARA T, NAKAMURA T, YAO D, et al S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration[J]. Nature, 2006, 441 (7092): 513- 517. |
| 24 | WANG C, LI W, REN J, et al Structural insights into the redox-regulated dynamic conformations of human protein disulfide isomerase[J]. Antioxid Redox Signal, 2013, 19 (1): 36- 45. |
| 25 | DARBY N J, CREIGHTON T E Functional properties of the individual thioredoxin-like domains of protein disulfide isomerase[J]. Biochemistry, 1995, 34 (37): 11725- 11735. |
| 26 | KLAPPA P, RUDDOCK L W, DARBY N J, et al The b' domain provides the principal peptide-binding site of protein disulfide isomerase but all domains contribute to binding of misfolded proteins[J]. EMBO J, 1998, 17 (4): 927- 935. |
| 27 | YAO Y, ZHOU Y, WANG C Both the isomerase and chaperone activities of protein disulfide isomerase are required for the reactivation of reduced and denatured acidic phospholipase A2[J]. EMBO J, 1997, 16 (3): 651- 658. |
| 28 | ELLGAARD L, RUDDOCK L W The human protein disulphide isomerase family: substrate interactions and functional properties[J]. EMBO Rep, 2005, 6 (1): 28- 32. |
| 29 | PAPP E, NARDAI G, STI C, et al Molecular chaperones, stress proteins and redox homeostasis[J]. Biofactors, 2003, 17 (1-4): 249- 257. |
| 30 | CHEN X, ZHANG X, LI C, et al S-nitrosylated protein disulfide isomerase contributes to mutant SOD1 aggregates in amyotrophic lateral sclerosis[J]. J Neurochem, 2013, 124 (1): 45- 58. |
| 31 | CHENG H, WANG L, WANG C C Domain a' of protein disulfide isomerase plays key role in inhibiting alpha-synuclein fibril formation[J]. Cell Stress Chaperones, 2010, 15 (4): 415- 421. |
| 32 | YAGI-UTSUMI M, SATOH T, KATO K Structural basis of redox-dependent substrate binding of protein disulfide isomerase[J]. Sci Rep, 2015, 5, 13909. |
| 33 | 余锦波, 张偲, 张则婷, 等 Alpha-突触核蛋白与完整线粒体相互作用的NMR研究[J]. 波谱学杂志, 2021, 38 (2): 164- 172. |
| 33 | YU J B, ZHANG C, ZHANG Z T, et al Interactions between α-synuclein and intact mitochondria studied by NMR[J]. Chinese J Magn Reson, 2021, 38 (2): 164- 172. |
| 34 | 寇新慧, 刘乙祥, 刘兴弘, 等 探测应答调控蛋白PhoBNF20D自由态中存在的Pre-Active构象[J]. 波谱学杂志, 2019, 36 (2): 164- 171. |
| 34 | KOU X H, LIU Y X, LIU X H, et al Visualizing the pre-active conformation of response regulator PhoBNF20D in its apo state[J]. Chinese J Magn Reson, 2019, 36 (2): 164- 171. |
| 35 | JAO C C, DER-SARKISSIAN A, CHEN J, et al Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling[J]. Proc Natl Acad Sci U S A, 2004, 101 (22): 8331- 8336. |
| 36 | HOYER W, ANTONY T, CHERNY D, et al Dependence of alpha-synuclein aggregate morphology on solution conditions[J]. J Mol Biol, 2002, 322 (2): 383- 393. |
| 37 | 戴晨晔, 刘买利, 李从刚 低盐和高盐环境下α-synuclein构象的19F NMR研究[J]. 波谱学杂志, 2015, 32 (1): 33- 44. |
| 37 | DAI C Y, LIU M L, LI C G Salt content-dependent conformational changes of alpha-synuclein studied by 19F NMR[J]. Chinese J Magn Reson, 2015, 32 (1): 33- 44. |
| 38 | PEI Y, LIU X, CHENG K, et al Backbone resonance assignment of PDI b'xa' domain construct[J]. Biomol NMR Assign, 2021, 15 (2): 409- 413. |
| 39 | DELAGLIO F, GRZESIEK S, VUISTER G W, et al NMRPipe: A multidimensional spectral processing system based on UNIX pipes[J]. J Biomol NMR, 1995, 6 (3): 277- 293. |
| 40 | LEE W, TONELLI M, MARKLEY J L NMRFAM-SPARKY: enhanced software for biomolecular NMR spectroscopy[J]. Bioinformatics, 2015, 31 (8): 1325- 1327. |
| 41 | WILLIAMSON, MIKE P Using chemical shift perturbation to characterise ligand binding[J]. Prog Nucl Magn Reson Spectrosc, 2013, 73, 1- 16. |
| 42 | ARAI M, FERREON J C, WRIGHT P E Quantitative analysis of multisite protein-ligand interactions by NMR: binding of intrinsically disordered p53 transactivation subdomains with the TAZ2 domain of CBP[J]. J Am Chem Soc, 2012, 134 (8): 3792- 3803. |
| 43 | DE OLIVEIRA G A P, SILVA J L Alpha-synuclein stepwise aggregation reveals features of an early onset mutation in Parkinson's disease[J]. Commun Biol, 2019, 2, 374. |
| 44 | CAMPIONI S, CARRET G, JORDENS S, et al The presence of an air-water interface affects formation and elongation of α-synuclein fibrils[J]. J Am Chem Soc, 2014, 136 (7): 2866- 2875. |
| 45 | CROKE R, PATIL S, QUEVREAUX J, et al NMR determination of pK(a) values in α-synuclein[J]. Protein sci, 2011, 20 (2): 256- 269. |
| 46 | SWEET R M, EISENBERG D Correlation of sequence hydrophobicities measures similarity in three-dimensional protein structure[J]. J Mol Biol, 1983, 171 (4): 479- 488. |
| 47 | BIANCALANA M, KOIDE S Molecular mechanism of thioflavin-T binding to amyloid fibrils[J]. Biochim Biophys Acta, 2010, 1804 (7): 1405- 1412. |
| 48 | KHURANA R, COLEMAN C, IONESCU-ZANETTI C, et al Mechanism of thioflavin T binding to amyloid fibrils[J]. J Struct Biol, 2005, 151 (3): 229- 238. |
| 49 | 陈艳华, 张则婷, 白佳, 等 PDI抑制α-synuclein纤维化聚集作用机制研究[J]. 波谱学杂志, 2017, 34 (2): 131- 136. |
| 49 | CHEN Y H, ZHANG Z T, BAI J, et al Inhibition mechanisms of protein disulfide isomerase on α-synuclein fibril aggregation[J]. Chinese J Magn Reson, 2017, 34 (2): 131- 136. |
| 50 | BYRNE LEE J, SIDHU A, WALLIS A K, et al Mapping of the ligand-binding site on the b′ domain of human PDI: interaction with peptide ligands and the x-linker region[J]. Biochem J, 2009, 423 (2): 209- 217. |
| 51 | YAN Y, ZHANG D, ZHOU P, et al HDOCK: a web server for protein-protein and protein-DNA/RNA docking based on a hybrid strategy[J]. Nucleic Acids Res, 2017, 45 (W1): W365- W373. |
| 52 | LARKIN M A, BLACKSHIELDS G, BROWN NP, et al Clustal W and Clustal X version 2.0[J]. Bioinformatics, 2007, 23 (21): 2947- 2948. |
| 53 | ROBERT X, GOUET P Deciphering key features in protein structures with the new ENDscript server[J]. Nucleic Acids Res, 2014, 42 (W1): W320- W324. |
| 54 | DOHERTY C P A, ULAMEC S M, MAYA-MARTINEZ R, et al A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function[J]. Nat Struct Mol Biol, 2020, 27 (3): 249- 259. |
/
| 〈 |
|
〉 |