Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles
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Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. / Heiss, Alexander; DuChesne, Alexander; Denecke, Bernd; Grötzinger, Joachim; Yamamoto, Kazuhiko; Renné, Thomas; Jahnen-Dechent, Willi.
In: J BIOL CHEM, Vol. 278, No. 15, 11.04.2003, p. 13333-41.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles
AU - Heiss, Alexander
AU - DuChesne, Alexander
AU - Denecke, Bernd
AU - Grötzinger, Joachim
AU - Yamamoto, Kazuhiko
AU - Renné, Thomas
AU - Jahnen-Dechent, Willi
PY - 2003/4/11
Y1 - 2003/4/11
N2 - Genetic evidence from mutant mice suggests that alpha(2)-HS glycoprotein/fetuin-A (Ahsg) is a systemic inhibitor of precipitation of basic calcium phosphate preventing unwanted calcification. Using electron microscopy and dynamic light scattering, we demonstrate that precipitation inhibition by Ahsg is caused by the transient formation of soluble, colloidal spheres, containing Ahsg, calcium, and phosphate. These "calciprotein particles" of 30-150 nm in diameter are initially amorphous and soluble but turn progressively more crystalline and insoluble in a time- and temperature-dependent fashion. Solubilization in Ahsg-containing calciprotein particles provides a novel conceptual framework to explain how insoluble calcium precipitates may be transported and removed in the bodies of mammals. Mutational analysis showed that the basic calcium phosphate precipitation inhibition activity resides in the amino-terminal cystatin-like domain D1 of Ahsg. A structure-function analysis of wild type and mutant forms of cystatin-like domains from Ahsg, full-length fetuin-B, histidine-rich glycoprotein, and kininogen demonstrated that Ahsg domain D1 is most efficient in inhibiting basic calcium phosphate precipitation. The computer-modeled domain structures suggest that a dense array of acidic residues on an extended beta-sheet of the cystatin-like domain Ahsg-D1 mediates efficient inhibition.
AB - Genetic evidence from mutant mice suggests that alpha(2)-HS glycoprotein/fetuin-A (Ahsg) is a systemic inhibitor of precipitation of basic calcium phosphate preventing unwanted calcification. Using electron microscopy and dynamic light scattering, we demonstrate that precipitation inhibition by Ahsg is caused by the transient formation of soluble, colloidal spheres, containing Ahsg, calcium, and phosphate. These "calciprotein particles" of 30-150 nm in diameter are initially amorphous and soluble but turn progressively more crystalline and insoluble in a time- and temperature-dependent fashion. Solubilization in Ahsg-containing calciprotein particles provides a novel conceptual framework to explain how insoluble calcium precipitates may be transported and removed in the bodies of mammals. Mutational analysis showed that the basic calcium phosphate precipitation inhibition activity resides in the amino-terminal cystatin-like domain D1 of Ahsg. A structure-function analysis of wild type and mutant forms of cystatin-like domains from Ahsg, full-length fetuin-B, histidine-rich glycoprotein, and kininogen demonstrated that Ahsg domain D1 is most efficient in inhibiting basic calcium phosphate precipitation. The computer-modeled domain structures suggest that a dense array of acidic residues on an extended beta-sheet of the cystatin-like domain Ahsg-D1 mediates efficient inhibition.
KW - Amino Acid Sequence
KW - Animals
KW - Blood Proteins
KW - Calcinosis
KW - Calcium
KW - Calcium-Binding Proteins
KW - Chickens
KW - Cloning, Molecular
KW - Cystatins
KW - Humans
KW - Light
KW - Mice
KW - Mice, Mutant Strains
KW - Models, Molecular
KW - Molecular Sequence Data
KW - Protein Conformation
KW - Protein Structure, Secondary
KW - Recombinant Proteins
KW - Scattering, Radiation
KW - Sequence Alignment
KW - Sequence Homology, Amino Acid
KW - alpha-2-HS-Glycoprotein
U2 - 10.1074/jbc.M210868200
DO - 10.1074/jbc.M210868200
M3 - SCORING: Journal article
C2 - 12556469
VL - 278
SP - 13333
EP - 13341
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 15
ER -