Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins

Hunter, Graeme; Hauschka, Peter V.; Poole, A. Robin; Rosenberg, Lawrence; Goldberg, Harvey A.

doi:10.1042/bj3170059

Cited by 554 publications

(505 citation statements)

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“…The inorganic core of dehydrated CPN samples has however been found to be amorphous, based on experimental results from a range of techniques including electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy (FTIR) and X-ray absorption spectroscopy (Cross et al 2005;Holt et al 1982Holt et al , 1996Holt et al and 2009Hunter et al 1996;Holt and Hukins 1991). Drying or radiation damage could nonetheless destroy crystalline order in the CPN.…”

Section: Introductionmentioning

confidence: 99%

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

et al. 2016

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There are abundant examples of nanoclusters and inorganic microcrystals in biology.Their study under physiologically relevant conditions remains challenging due to their instability, the requirements of sample preparation and other intrinsic limitations of the techniques used. Advantages of using neutron diffraction and contrast matching to characterize biomaterials are highlighted in this article. We have applied these methods and complementary techniques to search for long-range order within nanoclusters of calcium phosphate sequestered by bovine phosphopeptides, derived from osteopontin or casein. Hydrated and dried samples with different nanocluster radii were analyzed and compared to samples of known calcium phosphate phases. The absence of a distinct diffraction pattern from the nanoclusters is consistent with the presence of amorphous calcium phosphate structure.

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Section: Introductionmentioning

confidence: 99%

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

et al. 2016

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“…These Gla residues are thought to facilitate adsorption of osteocalcin to hydroxyapatite (10,14,15) and are located in the central, conserved portion of the molecule. In contrast, its N-terminal part exhibits considerable sequence variation (4,8,9,13).Initial studies showed that osteocalcin binds strongly to hydroxyapatite crystals (7) and affects mineral formation and mineral crystal growth in solution (16,17). Several studies also suggested a role for osteocalcin as a matrix signal for the recruitment and differentiation of osteoclasts (18-21).…”

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Structural Evidence of a Fourth Gla Residue in Fish Osteocalcin: Biological Implications^,

et al. 2005

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Osteocalcin is a small (45 amino acids) secreted protein found to accumulate in bone and dentin of many organisms by interacting with calcium and hydroxyapatite, through the presence of three γ-carboxylated residues. In this work, we describe the first X-ray crystal structure for a nonmammalian osteocalcin, obtained at 1.4 Å resolution, purified from the marine teleost fish Argyrosomus regius. The three-dimensional fit between the A. regius structure and that of the only other known X-ray structure, the porcine osteocalcin, revealed a superposition of the CR atoms of their metal chelating residues, Gla and Asp, showing that their spatial distribution is consistent with the interatomic distances of calcium cations in the hydroxyapatite crystals. In both structures, the protein forms a tight globular arrangement of their three R-helices while the remaining residues, at N-and C-terminal regions, have essentially no secondary structure characteristics. This study revealed the presence of a fourth γ-carboxylation at Glu 25 , not previously detected in the structure of the porcine osteocalcin or in any other of the sequentially characterized mammalian osteocalcins (human, cow, and rat). A confirmation of the fourth Gla residue in A. regius osteocalcin was achieved via LC-MS analysis. These four doubly charged residues are, together with Asp 24 , concentrated in a common surface region located on the same side of the molecule. This further suggests that the known high affinity of osteocalcin for bone mineral may be derived from the clustering of calcium binding sites on this surface of the molecules.Osteocalcin, also called bone Gla protein or BGP, 1 was the first member of the calcium binding and vitamin K-dependent protein family not associated with blood coagulation to be described, sequenced, and characterized (2, 3). This small protein of 46-50 amino acid residues (depending on the species) (4, 5) is secreted mainly by osteoblasts. It is also one of the most abundant (10-20%) noncollagenous proteins in bones of most vertebrates examined to date, from bony fish to mammals (depending on species, age, and site) (4,(6)(7)(8)(9).Conserved elements in all osteocalcin sequences examined to date include a single disulfide bond (Cys 17 -Cys 23 ) using Argyrosomus regius amino acid sequence numbering, and three γ-carboxyglutamic acid residues (Gla) located at positions 11, 15, and 18 (4, 9-13). These Gla residues are thought to facilitate adsorption of osteocalcin to hydroxyapatite (10,14,15) and are located in the central, conserved portion of the molecule. In contrast, its N-terminal part exhibits considerable sequence variation (4,8,9,13).Initial studies showed that osteocalcin binds strongly to hydroxyapatite crystals (7) and affects mineral formation and mineral crystal growth in solution (16,17). Several studies also suggested a role for osteocalcin as a matrix signal for the recruitment and differentiation of osteoclasts (18-21). However, the understanding of the physiological function of osteocalcin was su...

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“…Because of its unique calcium binding properties, early functional studies suggested that osteocalcin controlled the nucleation or deposition of mineral in bone (7)(8)(9)(10). However, more recent evidence indicates that osteocalcin is not related to events which allow mineral deposition to occur but, rather, that it participates in regulation of mineralization or bone turnover.…”

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The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy

Dowd

Rosen

et al. 2003

Biochemistry

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Structural information on osteocalcin or other noncollagenous bone proteins is very limited. We have solved the three-dimensional structure of calcium bound osteocalcin using 1 H 2D NMR techniques and proposed a mechanism for mineral binding. The protons in the 49 amino acid sequence were assigned using standard two-dimensional homonuclear NMR experiments. Distance constraints, dihedral angle constraints, hydrogen bonds, and 1 H and 13 C chemical shifts were all used to calculate a family of 13 structures. The tertiary structure of the protein consisted of an unstructured N terminus and a C-terminal loop (residues 16-49) formed by long-range hydrophobic interactions. Elements of secondary structure within residues 16-49 include type III turns (residues 20-25) and two α-helical regions (residues 27-35 and 41-44). The three Gla residues project from the same face of the helical turns and are surface exposed. The genetic algorithm-molecular dynamics simulation approach was used to place three calcium atoms on the NMR-derived structure. One calcium atom was coordinated by three side chain oxygen atoms, two from Asp30, and one from Gla24. The second calcium atom was coordinated to four oxygen atoms, two from the side chain in Gla 24, and two from the side chain of Gla 21. The third calcium atom was coordinated to two oxygen atoms of the side chain of Gla17. The best correlation of the distances between the uncoordinated Gla oxygen atoms is with the intercalcium distance of 9.43 Å in hydroxyapatite. The structure may provide further insight into the function of osteocalcin.The family of vitamin K-dependent γ-carboxylated calcium binding proteins is important in a variety of tissues and cellular functions. The formation of γ-carboxyglutamic acid (Gla) 1 in the liver derived blood clotting factors, for example, results in calcium-dependent conformational changes in the proteins and functionally important interactions with acidic phospholipid surfaces (1-3). The predominant Gla protein found in bone matrix is † Support for this project was provided by NIH Grant ES-02030 to T.D., support from the Division of Environmental Sciences,Children's Hospital at Montefiore (CHAM), at the Albert Einstein College of Medicine to T.D., and NIH Grant AR-38460 to C.G. *Corresponding author. Address: Montefiore Medical Center, Moses Bldg. Rm. 401, 111 East 210th Street, Bronx, NY, 10467. Phone: 718-920-2276. Fax: 718-920-4377. dowd@aecom.yu.edu. 1 Abbreviations: Gla, γ-carboxyglutamic acid; Fmoc, 9-flourenyl-methyloxycarbonyl; CD, circular dichroism; NMR, nuclear magnetic resonance; HSQC, heteronuclear single-quantum correlation; NOE, nuclear Overhauser effect; NOESY, NOE spectroscopy; rmsd, root-mean-square deviation; TOCSY, total correlation spectroscopy. HHS Public Access Author manuscriptBiochemistry. Author manuscript; available in PMC 2015 July 28. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript osteocalcin (4, 5), a small Ca 2+ binding protein containing three Gla residues which are thought to facil...

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Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins

Cited by 554 publications

References 47 publications

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

Structural Evidence of a Fourth Gla Residue in Fish Osteocalcin: Biological Implications^,

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy

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Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins

Cited by 554 publications

References 47 publications

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

Structural studies of hydrated samples of amorphous calcium phosphate and phosphoprotein nanoclusters

Structural Evidence of a Fourth Gla Residue in Fish Osteocalcin: Biological Implications,

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using 1H NMR Spectroscopy

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Structural Evidence of a Fourth Gla Residue in Fish Osteocalcin: Biological Implications^,

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy