Aromaticity at position 39 in α-synuclein: A modulator of amyloid fibril assembly and membrane-bound conformations

被引：8

作者：

Buratti, Fiamma A. ^{[1
]}

Boeffinger, Nicola ^{[2
,3
]}

Garro, Hugo A. ^{[1
,4
]}

Flores, Jesica S. ^{[1
]}

Hita, Francisco J. ^{[1
]}

do Carmo Goncalves, Phelippe ^{[1
]}

dos Reis Copello, Federico ^{[5
]}

Lizarraga, Leonardo ^{[5
]}

Rossetti, Giulia ^{[6
,7
,8
,9
]}

Carloni, Paolo ^{[6
,7
,10
,11
]}

Zweckstetter, Markus ^{[2
,12
]}

Outeiro, Tiago F. ^{[13
,14
,15
]}

Eimer, Stefan ^{[3
]}

Griesinger, Christian ^{[2
]}

Fernandez, Claudio O. ^{[1
,2
]}

机构：

[1] Univ Nacl Rosario, Max Planck Lab Struct Biol Chem & Mol Biophys Ros, MPINAT,MPG,Ctr Estudios Interdisciplinarios, MPLbioR UNR MPINAT Partner Lab Max Planck Inst Mu, S2002LRK, Rosario, Argentina

[2] Max Planck Inst Multidisciplinary Sci, Dept NMR Based Struct Biol, Gottingen, Germany

[3] Goethe Univ Frankfurt, Inst Cell Biol & Neurosci, Dept Struct Cell Biol, Frankfurt, Germany

[4] UNSL INTEQUI CONICET, Area Quim Orgdn, San Luis, Argentina

[5] Ctr Invest Bionanociencias CIBION CONICET, Buenos Aires, DF, Argentina

[6] Inst Neurosci & Med INM 9, Computat Biomed, Julich, Germany

[7] Inst Adv Simulat IAS 5, Julich, Germany

[8] Rhein Westfal TH Aachen, Univ Hosp Aachen, Dept Neurol, Aachen, Germany

[9] Julich Supercomp Ctr JSC, Julich, Germany

[10] Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, Aachen, Germany

[11] Forschungszentrum Julich, Inst Neurosci & Med INM 11, Julich, Germany

[12] German Ctr Neurodegenerat Dis DZNE, Gottingen, Germany

[13] Univ Med Ctr Gottingen, Ctr Biostruct Imaging Neurodegenerat, Dept Expt Neurodegenerat, Gottingen, Germany

[14] Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[15] Deutsch Zentrum Neurodegenerat Erkrankungen DZNE, Gottingen, Germany

来源：

PROTEIN SCIENCE | 2022年 / 31卷 / 07期

关键词：

amyloid fibril; fluorescence and confocal microscopy; lipid interaction; NMR; sequence motifs; alpha-synuclein; PARKINSONS-DISEASE; TERMINAL REGION; LEWY BODIES; RANDOM COIL; C-ABL; BINDING; AGGREGATION; DEMENTIA; NMR; PHOSPHORYLATION;

D O I：

10.1002/pro.4360

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Recent studies revealed that molecular events related with the physiology and pathology of alpha S might be regulated by specific sequence motifs in the primary sequence of alpha S. The importance of individual residues in these motifs remains an important open avenue of investigation. In this work, we have addressed the structural details related to the amyloid fibril assembly and lipid-binding features of alpha S through the design of site-directed mutants at position 39 of the protein and their study by in vitro and in vivo assays. We demonstrated that aromaticity at position 39 of alpha S primary sequence influences strongly the aggregation properties and the membrane-bound conformations of the protein, molecular features that might have important repercussions for the function and dysfunction of alpha S. Considering that aggregation and membrane damage is an important driver of cellular toxicity in amyloid diseases, future work is needed to link our findings with studies based on toxicity and neuronal cell death. Brief statement outlining significance: Modulation by distinct sequential motifs and specific residues of alpha S on its physiological and pathological states is an active area of research. Here, we demonstrated that aromaticity at position 39 of alpha S modulates the membrane-bound conformations of the protein, whereas removal of aromatic functionality at position 39 reduces strongly the amyloid assembly in vitro and in vivo. Our study provides new evidence for the modulation of molecular events related with the physiology and pathology of alpha S.

引用

页数：12

共 57 条

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