Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis

P. John Hart; Hongbin Liu; Matteo Pellegrini; Aram M. Nersissian; Edith B. Gralla; Joan S. Valentine; David Eisenberg

doi:10.1002/pro.5560070302

Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis

P. John Hart, Hongbin Liu, Matteo Pellegrini, Aram M. Nersissian, Edith B. Gralla, Joan S. Valentine, David Eisenberg

Department of Biochemistry & Structural Biology

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

Abstract

The X-ray crystal structure of a human copper/zinc superoxide dismutase mutant (G37R CuZnSOD) found in some patients with the inherited form of Lou Gehrig's disease (FALS) has been determined to 1.9 Å resolution. The two SOD subunits have distinct environments in the crystal and are different in structure at their copper binding sites. One subunit (subunit(intact)) shows a four-coordinate ligand geometry of the copper ion, whereas the other subunit (subunit(broken)) shows a three-coordinate geometry of the copper ion. Also, subunit(intact) displays higher atomic displacement parameters for backbone atoms (= 30 ± 10 Å²) than subunit(broken) (= 24 ± 11 Å²). This structure is the first CuZnSOD to show large differences between the two subunits. Factors that may contribute to these differences are discussed and a possible link of a looser structure to FALS is suggested.

Original language	English (US)
Pages (from-to)	545-555
Number of pages	11
Journal	Protein Science
Volume	7
Issue number	3
DOIs	https://doi.org/10.1002/pro.5560070302
State	Published - Mar 1998

Keywords

Amyotrophic lateral sclerosis
Apoptosis
Lou Gehrig's disease
Motor neuron
Neurodegeneration
Oxidative damage
Superoxide dismutase
X-ray crystallography

ASJC Scopus subject areas

Molecular Biology
Biochemistry

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10.1002/pro.5560070302

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@article{c2694ec3824b4853868c2394a7bcdc48,

title = "Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis",

abstract = "The X-ray crystal structure of a human copper/zinc superoxide dismutase mutant (G37R CuZnSOD) found in some patients with the inherited form of Lou Gehrig's disease (FALS) has been determined to 1.9 {\AA} resolution. The two SOD subunits have distinct environments in the crystal and are different in structure at their copper binding sites. One subunit (subunit(intact)) shows a four-coordinate ligand geometry of the copper ion, whereas the other subunit (subunit(broken)) shows a three-coordinate geometry of the copper ion. Also, subunit(intact) displays higher atomic displacement parameters for backbone atoms (= 30 ± 10 {\AA}2) than subunit(broken) (= 24 ± 11 {\AA}2). This structure is the first CuZnSOD to show large differences between the two subunits. Factors that may contribute to these differences are discussed and a possible link of a looser structure to FALS is suggested.",

keywords = "Amyotrophic lateral sclerosis, Apoptosis, Lou Gehrig's disease, Motor neuron, Neurodegeneration, Oxidative damage, Superoxide dismutase, X-ray crystallography",

author = "Hart, {P. John} and Hongbin Liu and Matteo Pellegrini and Nersissian, {Aram M.} and Gralla, {Edith B.} and Valentine, {Joan S.} and David Eisenberg",

note = "Funding Information: We are indebted to the patients for their participation. Robert Kelly is warmly thanked for reviewing the manuscript. This work was supported by the Fondation de la Recherche M{\'e}dicale, the SESERAC, and the R{\'e}gion Rh{\^o}ne-Alpes. C{\'e}cile Guichard is a student of the Ecole Pratique des Hautes Etudes, Paris. ",

year = "1998",

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doi = "10.1002/pro.5560070302",

language = "English (US)",

volume = "7",

pages = "545--555",

journal = "Protein Science",

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publisher = "Cold Spring Harbor Laboratory Press",

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T1 - Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis

AU - Hart, P. John

AU - Liu, Hongbin

AU - Pellegrini, Matteo

AU - Nersissian, Aram M.

AU - Gralla, Edith B.

AU - Valentine, Joan S.

AU - Eisenberg, David

N1 - Funding Information: We are indebted to the patients for their participation. Robert Kelly is warmly thanked for reviewing the manuscript. This work was supported by the Fondation de la Recherche Médicale, the SESERAC, and the Région Rhône-Alpes. Cécile Guichard is a student of the Ecole Pratique des Hautes Etudes, Paris.

PY - 1998/3

Y1 - 1998/3

N2 - The X-ray crystal structure of a human copper/zinc superoxide dismutase mutant (G37R CuZnSOD) found in some patients with the inherited form of Lou Gehrig's disease (FALS) has been determined to 1.9 Å resolution. The two SOD subunits have distinct environments in the crystal and are different in structure at their copper binding sites. One subunit (subunit(intact)) shows a four-coordinate ligand geometry of the copper ion, whereas the other subunit (subunit(broken)) shows a three-coordinate geometry of the copper ion. Also, subunit(intact) displays higher atomic displacement parameters for backbone atoms (= 30 ± 10 Å2) than subunit(broken) (= 24 ± 11 Å2). This structure is the first CuZnSOD to show large differences between the two subunits. Factors that may contribute to these differences are discussed and a possible link of a looser structure to FALS is suggested.

AB - The X-ray crystal structure of a human copper/zinc superoxide dismutase mutant (G37R CuZnSOD) found in some patients with the inherited form of Lou Gehrig's disease (FALS) has been determined to 1.9 Å resolution. The two SOD subunits have distinct environments in the crystal and are different in structure at their copper binding sites. One subunit (subunit(intact)) shows a four-coordinate ligand geometry of the copper ion, whereas the other subunit (subunit(broken)) shows a three-coordinate geometry of the copper ion. Also, subunit(intact) displays higher atomic displacement parameters for backbone atoms (= 30 ± 10 Å2) than subunit(broken) (= 24 ± 11 Å2). This structure is the first CuZnSOD to show large differences between the two subunits. Factors that may contribute to these differences are discussed and a possible link of a looser structure to FALS is suggested.

KW - Amyotrophic lateral sclerosis

KW - Apoptosis

KW - Lou Gehrig's disease

KW - Motor neuron

KW - Neurodegeneration

KW - Oxidative damage

KW - Superoxide dismutase

KW - X-ray crystallography

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Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis

Abstract

Keywords

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