Heparin remodels the microtubule-binding repeat R3 of Tau protein towards fibril-prone conformations

Dong, Xuewei1,2; Qi, Ruxi3; Qiao, Qin4; Li, Xuhua5; Li, Fangying1,2; Wan, Jiaqian6; Zhang, Qingwen6; Wei, Guanghong1,2

2021-08-01

10.1039/d1cp02651h

PHYSICAL CHEMISTRY CHEMICAL PHYSICS   影响因子和分区

1463-9076

1463-9084

Abnormal aggregation of proteins into pathological amyloid fibrils is implicated in a wide range of devastating human neurodegenerative diseases. Intracellular fibrillary inclusions formed by Tau protein are characterized as the hallmark of tauopathies, including Alzheimer's disease and frontotemporal dementia. Heparin has been often used to trigger Tau aggregation in in vitro studies. However, the conformational changes induced by heparin and the underlying mechanism of promotion of Tau aggregation by heparin are not well understood. Structural characterization of Tau oligomers in the early stage of fibrillation is of great importance but remains challenging due to their dynamic and heterogeneous nature. R3, the third microtubule-binding repeat of Tau, contains the fibril-nucleating core (PHF6) and is crucial for Tau aggregation. In this study, utilizing extensive all-atom replica-exchange molecular dynamic simulations, we explored the conformational ensembles of R3 monomer/dimer in the absence and presence of heparin. Our results show that without heparin, both monomeric and dimeric R3 preferentially adopt collapsed beta-sheet-containing conformations and PHF6 plays an important role in the formation of interchain beta-sheet structures, while in the presence of heparin, R3 can populate relatively extended disordered states where chain dimension is similar to that of R3 in Tau filaments. Through electrostatic, hydrogen-bonding and hydrophobic interactions, heparin has a preference for interacting with residues V306/Q307/K317/K321/H329/H330/K331 which distribute throughout the entire sequence of R3, in turn acting as a template to extend R3 conformations. More importantly, heparin alters intramolecular/intermolecular interaction patterns of R3 and increases the intermolecular contact regions. Our results suggest that heparin remodels the conformations of R3 towards fibril-prone structures by increasing chain dimension and intermolecular contact regions, which may shed light on the atomic mechanism of heparin-induced amyloid fibrillization of Tau protein.

SCI ; EI

英语

其他

National Key Research and Development Program of China[2016YFA0501702] ; National Natural Science Foundation of China[12074079,11804054] ; Guangdong Basic and Applied Basic Research Foundation[2019A1515110090]

Chemistry ; Physics

Chemistry, Physical ; Physics, Atomic, Molecular & Chemical

WOS:000693601800001

ROYAL SOC CHEMISTRY

20213910960690

Conformations ; Dynamics ; Glycoproteins ; Hydrogen bonds ; Hydrophobicity ; Molecular dynamics ; Neurodegenerative diseases ; Proteins

Medicine and Pharmacology:461.6 ; Biology:461.9 ; Physical Chemistry:801.4 ; Organic Compounds:804.1 ; Organic Polymers:815.1.1 ; Physical Properties of Gases, Liquids and Solids:931.2

CHEMISTRY

Web of Science

1.Fudan Univ, Minist Educ, Dept Phys, State Key Lab Surface Phys, Shanghai 200438, Peoples R China
2.Fudan Univ, Key Lab Computat Phys Sci, Minist Educ, Shanghai 200438, Peoples R China
3.Southern Univ Sci & Technol, CryoEM Ctr, Shenzhen 518055, Peoples R China
4.Fudan Univ, Digital Med Res Ctr, Sch Basic Med Sci, Shanghai Key Lab Med Imaging Comp & Comp Assisted, Shanghai 200032, Peoples R China
5.Xi An Jiao Tong Univ, Sch Phys, MOE Key Lab Nonequilibrium Synth & Modulat Conden, Xian 710049, Peoples R China
6.Shanghai Univ Sport, Coll Phys Educ & Training, Shanghai 200438, Peoples R China

Dong, Xuewei,Qi, Ruxi,Qiao, Qin,et al. Heparin remodels the microtubule-binding repeat R3 of Tau protein towards fibril-prone conformations[J]. PHYSICAL CHEMISTRY CHEMICAL PHYSICS,2021,23:20406-20418.

Dong, Xuewei.,Qi, Ruxi.,Qiao, Qin.,Li, Xuhua.,Li, Fangying.,...&Wei, Guanghong.(2021).Heparin remodels the microtubule-binding repeat R3 of Tau protein towards fibril-prone conformations.PHYSICAL CHEMISTRY CHEMICAL PHYSICS,23,20406-20418.

Dong, Xuewei,et al."Heparin remodels the microtubule-binding repeat R3 of Tau protein towards fibril-prone conformations".PHYSICAL CHEMISTRY CHEMICAL PHYSICS 23(2021):20406-20418.