DOI: 10.1073/pnas.95.7.3478. Thiolate ligands in metallothionein confer redox activity on zinc clusters

Thiolate ligands in metallothionein confer redox activity on zinc clusters

10.1073/pnas.95.7.3478

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

We postulate a novel and general mechanism in which the redox-active sulfur donor group of cyst(e)ine confers oxidoreductive characteristics on stable zinc sites in proteins. Thus, the present, an earlier, and accompanying manuscripts [Maret, W., Larsen, K. S. & Vallee, B. L. (1997) Proc. Natl. Acad. Sci. USA 94, 2233–2237; Jiang, L.-J., Maret, W. & Vallee, B. L. (1998) Proc. Natl. Acad. Sci. USA 95, 3483–3488; and Jacob, C., Maret, W. & Vallee, B. L. (1998) Proc. Natl. Acad. Sci. USA 95, 3489–3494] demonstrate that the interactive network featuring multiple zinc/sulfur bonds as found in the clusters of metallothionein (MT) constitutes a coordination unit critical for the concurrent oxidation of cysteine ligands and the ensuing release of zinc. The low position of MT (<−366 mV) on a scale of redox reagents allows its effective oxidation by relatively mild cellular oxidants, in particular disulfides. When MT is exposed to an excess of dithiodipyridine, all of its 20 cysteines are oxidized within 1 hr with the concomitant release of all 7 zinc atoms; similarly, the thiol/disulfide oxidoreductase DsbA reacts stoichiometrically with MT to release zinc. Zinc and sulfur ligands in the clusters are in a spatial arrangement that seemingly favors disulfide bond formation. Jointly, this and the above-mentioned manuscripts conclude that the control of cellular zinc distribution as a function of the energy state of the cell is the long sought role of MT. This specific MT function renders dubious the widely held belief that MT primarily scavenges radicals or detoxifies metals and is consistent with the frequent use of cysteine as a zinc ligand in proteins as a means of both tight and weak zinc binding of thiols and disulfides, respectively. Thus, we relate changes in the reducing power of the cell to the stability of the zinc/sulfur network in MT and the relative mobility of zinc and its control.

Bibliography

Maret, W., & Vallee, B. L. (1998). Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proceedings of the National Academy of Sciences, 95(7), 3478â3482.

Authors 2

Wolfgang Maret (first)
Bert L. Vallee (additional)

References 42 Referenced 481

A H Robbins, D E McRee, M Williamson, S A Collett, N H Xuong, W F Furey, B C Wang, C D Stout J Mol Biol 221, 1269–1293 (1991). / J Mol Biol by Robbins A H (1991)
10.1016/0022-2836(88)90644-4
10.1007/978-3-0348-6493-0_1
10.1007/978-3-0348-6784-9_1
B L Vallee, W Maret Metallothionein III, eds K T Suzuki, N Imura, M Kimura (Birkhäuser, Basel), pp. 1–27 (1993). / Metallothionein III by Vallee B L (1993)
10.1016/0076-6879(91)05077-9
J H R Kägi Metallothionein III, eds K T Suzuki, N Imura, M Kimura (Birkhäuser, Basel), pp. 29–55 (1993). / Metallothionein III by Kägi J H R (1993)
J D Otvos, X Liu, H Li, G Shen, M Basti Metallothionein III, eds K T Suzuki, N Imura, M Kimura (Birkhäuser, Basel), pp. 57–74 (1993). / Metallothionein III by Otvos J D (1993)
10.1073/pnas.94.6.2233
10.1073/pnas.91.1.237
10.1016/0197-0186(94)00173-R
10.1073/pnas.95.7.3483
10.1073/pnas.95.7.3489
10.1016/0076-6879(91)05082-7
10.1016/0076-6879(91)05137-K
10.1021/ic00328a012
10.1016/0003-9861(92)90384-9
, ed R C Weast (CRC, 61st Ed., Boca Raton, FL) Handbook of Chemistry and Physics, pp. D-155–D-157 (1980). / Handbook of Chemistry and Physics by Weast R C (1980)
, ed G D Fasman (CRC, 3rd Ed., Boca Raton, FL) Handbook of Biochemistry and Molecular Biology: Physical and Chemical Data 1, 122–130 (1976). / Handbook of Biochemistry and Molecular Biology: Physical and Chemical Data by Fasman G D (1976)
10.1016/0076-6879(95)51107-5
10.1006/abbi.1996.0452
10.1016/0167-4838(85)90098-6
10.1006/bbrc.1994.1564
10.1042/bj3170389
10.1016/0024-3205(93)90019-Y
10.1016/0162-0134(93)80028-8
10.1016/0302-4598(88)85010-4
10.1126/science.1523409
10.1074/jbc.272.49.30780
C G Kuehn, S S Isied Prog Inorg Chem 27, 153–221 (1980). / Prog Inorg Chem by Kuehn C G (1980)
10.1096/fasebj.7.15.8262333
10.1006/abbi.1997.0334
10.1016/0891-5849(93)90029-T
10.1021/tx950109y
10.1021/ja01574a064
10.1152/physrev.1993.73.1.79
10.1002/j.1460-2075.1995.tb07042.x
10.1002/j.1460-2075.1996.tb00527.x
10.1073/pnas.93.25.14934
10.1016/S0955-0674(97)80036-1
10.1038/41343
10.1038/ng1197-292

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:40 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 4:50 p.m.)
Indexed	6 days, 20 hours ago (Aug. 22, 2025, 12:45 a.m.)
Issued	27 years, 4 months ago (March 31, 1998)
Published	27 years, 4 months ago (March 31, 1998)
Published Online	27 years, 4 months ago (March 31, 1998)
Published Print	27 years, 4 months ago (March 31, 1998)

Funders 0

None

BibTeX

@article{Maret_1998, title={Thiolate ligands in metallothionein confer redox activity on zinc clusters}, volume={95}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.95.7.3478}, DOI={10.1073/pnas.95.7.3478}, number={7}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Maret, Wolfgang and Vallee, Bert L.}, year={1998}, month=mar, pages={3478–3482} }

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