Bone sialoprotein
Encyclopedia
Bone sialoprotein is a component of mineralized tissues
such as bone
, dentin
, cementum
and calcified cartilage
. BSP is a significant component of the bone extracellular matrix and has been suggested to constitute approximately 8% of all non-collagenous proteins found in bone and cementum. BSP, a SIBLING protein
, was originally isolated from bovine cortical bone as a 23-kDa glycopeptide with high sialic acid
content.
The human variant of BSP is called bone sialoprotein 2 also known as cell-binding sialoprotein or integrin-binding sialoprotein and is encoded by the IBSP gene
.
, which is a considerable deviation from the predicted weight (based on cDNA
sequence) of approximately 33 kDa. The mammalian BSP cDNAs encode for proteins averaging 327 amino acids, which includes the 16-residue preprotein secretory signal peptide. Among the mammalian cDNAs currently characterized, there is an approximate 45% conservation of sequence identity and a further 10-23% conservative substitution. The protein is highly acidic (pKa of ~ 3.9) and contains a large amount of Glu residues, constituting ~22% of the total amino acid.
Secondary structure prediction and hydrophobicity analyses suggest that the primary sequence of BSP has an open, flexible structure with the potential to form regions of α-helix
and some β-sheet
. However, the majority of studies have demonstrated that BSP has no α-helical or β-sheet structure by 1D NMR and circular dichroism. Analysis of native protein by electron microscopy confirm that the protein has an extended structure approximately 40 nm in length. This flexible conformation suggests that the protein has few structural domains, however it has been suggested that there may be several spatially-segmented functional domains including a hydrophobic collagen
-binding domain (rattus norvegicus residues 36-57), a hydroxyapatite-nucleating region of contiguous glutamic acid residues (rattus norvegicus residues 78-85, 155-164) and a classical integrin
-binding motif (RGD) near the C-terminal (rattus norvegicus residues 288-291).
BSP has been demonstrated to be extensively post-translationally modified, with carbohydrates and other modifications comprising approximately 50% of the molecular weight of the native protein. These modifications, which include N- and O-linked glycosylation
, tyrosine sulfation
and serine and threonine phosphorylation
, make the protein highly heterogeneous.
crystals. As the apatite forms along the collagen fibres within the extracellular matrix, BSP could then help direct, redirect or inhibit the crystal growth.
Additional roles of BSP are MMP-2 activation, angiogenesis, and protection from complement-mediated cell lysis. Regulation of the BSP gene is important to bone matrix mineralization and tumor growth in bone.
Mineralized tissues
Mineralized tissues are biological tissues that incorporate minerals into soft matrices. Typically these tissues form a protective shield or structural support...
such as bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
, dentin
Dentin
Dentine is a calcified tissue of the body, and along with enamel, cementum, and pulp is one of the four major components of teeth. Usually, it is covered by enamel on the crown and cementum on the root and surrounds the entire pulp...
, cementum
Cementum
Cementum is a specialized calcified substance covering the root of a tooth. Cementum is excreted by cells called cementoblasts within the root of the tooth and is thickest at the root apex. These cementoblasts develop from undifferentiated mesenchymal cells in the connective tissue of the dental...
and calcified cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
. BSP is a significant component of the bone extracellular matrix and has been suggested to constitute approximately 8% of all non-collagenous proteins found in bone and cementum. BSP, a SIBLING protein
SIBLING proteins
The family of non-collagenous proteins known as SIBLING proteins, standing for small integrin-binding ligand, N-linked glycoprotein, included proteins that exist in the extracellular matrix of bone and dentin and are believed to play key roles in the mineralization of these two substances.The...
, was originally isolated from bovine cortical bone as a 23-kDa glycopeptide with high sialic acid
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
content.
The human variant of BSP is called bone sialoprotein 2 also known as cell-binding sialoprotein or integrin-binding sialoprotein and is encoded by the IBSP gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Structure
Native BSP has an apparent molecular weight of 60-80 kDa based on SDS-PAGESDS-PAGE
SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis, describes a collection of related techniques widely used in biochemistry, forensics, genetics and molecular biology to separate proteins according to their electrophoretic mobility...
, which is a considerable deviation from the predicted weight (based on cDNA
Complementary DNA
In genetics, complementary DNA is DNA synthesized from a messenger RNA template in a reaction catalyzed by the enzyme reverse transcriptase and the enzyme DNA polymerase. cDNA is often used to clone eukaryotic genes in prokaryotes...
sequence) of approximately 33 kDa. The mammalian BSP cDNAs encode for proteins averaging 327 amino acids, which includes the 16-residue preprotein secretory signal peptide. Among the mammalian cDNAs currently characterized, there is an approximate 45% conservation of sequence identity and a further 10-23% conservative substitution. The protein is highly acidic (pKa of ~ 3.9) and contains a large amount of Glu residues, constituting ~22% of the total amino acid.
Secondary structure prediction and hydrophobicity analyses suggest that the primary sequence of BSP has an open, flexible structure with the potential to form regions of α-helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and some β-sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
. However, the majority of studies have demonstrated that BSP has no α-helical or β-sheet structure by 1D NMR and circular dichroism. Analysis of native protein by electron microscopy confirm that the protein has an extended structure approximately 40 nm in length. This flexible conformation suggests that the protein has few structural domains, however it has been suggested that there may be several spatially-segmented functional domains including a hydrophobic collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
-binding domain (rattus norvegicus residues 36-57), a hydroxyapatite-nucleating region of contiguous glutamic acid residues (rattus norvegicus residues 78-85, 155-164) and a classical integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
-binding motif (RGD) near the C-terminal (rattus norvegicus residues 288-291).
BSP has been demonstrated to be extensively post-translationally modified, with carbohydrates and other modifications comprising approximately 50% of the molecular weight of the native protein. These modifications, which include N- and O-linked glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
, tyrosine sulfation
Sulfation
Sulfation in biochemistry is the enzyme-catalyzed addition of sulfate to another molecule. It often refers to a phase II enzyme reaction. This biotransformation process uses its cosubstrate 3'-phosphoadenosine-5'-phosphosulfate to transfer sulfate to a xenobiotic...
and serine and threonine phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
, make the protein highly heterogeneous.
Function
The amount of BSP in bone and dentin is roughly equal, however the function of BSP in these mineralized tissues is not known. One possibility is that BSP acts as a nucleus for the formation of the first apatiteApatite
Apatite is a group of phosphate minerals, usually referring to hydroxylapatite, fluorapatite, chlorapatite and bromapatite, named for high concentrations of OH−, F−, Cl− or Br− ions, respectively, in the crystal...
crystals. As the apatite forms along the collagen fibres within the extracellular matrix, BSP could then help direct, redirect or inhibit the crystal growth.
Additional roles of BSP are MMP-2 activation, angiogenesis, and protection from complement-mediated cell lysis. Regulation of the BSP gene is important to bone matrix mineralization and tumor growth in bone.