Low micromolar zinc accelerates the fibrillization of human tau via bridging of Cys-291 and Cys-322.
A hallmark of a group of neurodegenerative diseases such as Alzheimer disease is the formation of neurofibrillary tangles, which are principally composed of bundles of filaments formed by microtubule-associated protein Tau. Clarifying how natively unstructured Tau protein forms abnormal aggregates is of central importance for elucidating the etiology of these diseases. There is considerable evidence showing that zinc, as an essential element that is highly concentrated in brain, is linked to the development or progression of these diseases. Herein, by using recombinant human Tau fragment Tau(244-372) and its mutants, we have investigated the effect of zinc on the aggregation of Tau. Low micromolar concentrations of Zn(2+) dramatically accelerate fibril formation of wild-type Tau(244-372) under reducing conditions, compared with no Zn(2+). Higher concentrations of Zn(2+), however, induce wild-type Tau(244-372) to form granular aggregates in reducing conditions. Moreover, these non-fibrillar aggregates assemble into mature Tau filaments when Zn(2+) has been chelated by EDTA. Unlike wild-type Tau(244-372), low micromolar concentrations of Zn(2+) have no obvious effects on fibrillization kinetics of single mutants C291A and C322A and double mutant C291A/C322A under reducing conditions. The results from isothermal titration calorimetry show that one Zn(2+) binds to one Tau molecule via tetrahedral coordination to Cys-291 and Cys-322 as well as two histidines, with moderate, micromolar affinity. Our data demonstrate that low micromolar zinc accelerates the fibrillization of human Tau protein via bridging Cys-291 and Cys-322 in physiological reducing conditions, providing clues to understanding the relationship between zinc dyshomeostasis and the etiology of neurodegenerative diseases.
Mo
Zhong-Ying
ZY
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
Zhu
Ying-Zhu
YZ
Zhu
Hai-Li
HL
Fan
Jun-Bao
JB
Chen
Jie
J
Liang
Yi
Y
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D003545:Cysteine / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism; D006801:Humans; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D015032:Zinc / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D004220:Disulfides; C054369:MAPT protein, human; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016875:tau Proteins; D015032:Zinc; D003545:Cysteine