Extracellular calcium binding proteins

The third class of extracellular calcium binding proteins are the salivary acidic proline-rich proteins. The major proteins have been named salivary proteins A and C. These proteins bind to and inhibit the formation of hydroxylapatite and it has been suggested that they function to aid in the maintenance of the integrity of the teeth. Calcium is bound by the salivary proteins by a series of negatively charged phosphoserine residues. Treatment with phosphatases to selectively remove the phosphoryl-moieties from phosphoserine dramatically reduces calcium binding affinity. 

The first class of membranous calcium binding proteins are represented by those proteins involved in the generation and modulation of the calcium signal (Table III). The calcium signal is regulated by the uptake and release of calcium across the three major membrane systems which bound the cytoplasm (the plasma membrane, the 

The observation that mitochondria can take up extremely large amounts of calcium in an energy dependent manner has for many years focused attention on these organelles as the major intracellular store controlling cytosolic calcium (with the exception of muscle where the sarcoplasmic reticulum was considered to be the key organelle). 

The inner membrane of the mitochondria contains two important calcium binding proteins a calcium importer that moves calcium from the cytoplasm to the mi- 

Protein Organelle Tissue Km(Ca2 ) mM Vmax of transport nmol Ca2+/mg protein 

The total concentration of calcium in the blood plasma is ca. 2 mM, and about half of it is bound to proteins, mainly serum albumin. This high calcium concentration is typical for all extracellular fluids, in stark contrast to the very low free calcium concentration in resting cells. One might therefore be led to believe that there is no specific function of calcium in the extracellular fluids. This is certainly not true. It has been known for almost a century that calcium is critical for blood coagulation, and it is also well known that calcium is a major component in our skeleton. It is, however, also obvious that the requirement for a protein to be calcium binding in a milieu with free calcium at 1 mM is very different from one with calcium at p.M levels. 

Cone snails produce biologically active peptides to paralyze their prey. The peptides are known as conotoxins (176-178). Most of them are small and stabilized by disulfide bonds. Two unusual members of the conotoxin family are conantokin G from Conus geographica (179) and conantokin T from Conus tulipa (180), which lack disulfide bonds but are rich in y-carboxyglutamic acid residues  

The role of the Gla residues is not yet fully understood, but a synthetic conantokin peptide with Glu instead of Gla has been shown to be inactive. However, it is still not clear whether Ca2+ is essential for biological functioning of the conantokin peptides (181, 182). There appears to be no thorough study of the calcium ion binding to these peptides, though CD spectroscopy has been used to study the change in helical content as a function of calcium concentration (183). The 

The epidermal growth factor (EGF)-like domains are approximately 45 amino acids long and contain six cysteine residues that are paired in a characteristic manner, 1 to 3, 2 to 4, and 5 to 6, with a double-stranded /3-sheet as the main structural feature. The EGF domain has been found in a wide variety of proteins including these involved in blood coagulation, fibrinolysis, neuronal development, and 

The structures of several isolated EGF domains have been determined by NMR, the first one more than 10 years ago (220-232). These structures are all quite similar, revealing a domain structure consisting of two relatively independent subdomains. The N terminal 

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Extinction difference/intensity difference diagrams for polymetalates, 19 252, 253 Extracellular calcium-binding proteins, 46 442, 470-485... 

There are several types of extracellular calcium-binding proteins. The majority of these proteins such as cadherins, integrins and growth factors, are from eukaryotic systems. 

E, y-Carboxyglutamic Acid Sites Extracellular Calcium-Binding Proteins... 

Much discussion of vitamin D focuses on bone health, though this is by no means the only focus on vitamin D action. One result of l,25(OH)2D action is the upregulation of the synthesis of a calcium-binding protein whose function is to transport dietary calcium across the intestinal mucosa and into the systemic circulation. Phosphate accompanies the calcium. This has the effect of increasing the fraction of dietary calcium that is actually absorbed and is, therefore, potentially useful for bone formation. In addition, l,25(OH2)D has the effect of mobilizing calcium from bone. Both actions tend to raise the extracellular level of calcium. 

A wide range of calcium-binding proteins have been isolated from intracellular and extracellular sources. 11S 119 209,210 They are involved in the storage of calcium, the buffering of calcium concentrations and the triggering of a wide range of processes involving membrane transport, secretion... 

The controlled deposition of calcium salts is essential for the development of extracellular structures such as bones, teeth and shell. The process begins with uptake of calcium in the intestine, followed by transport, and then the laying down of structures. A complex system is necessary for the control of all these stages, and involves, for example, vitamin D, parathyroid hormone, calcium-binding proteins for transport, and a range of other proteins and polysaccharides for ordered deposition. Precipitation of calcium salts in the incorrect location can result in stone formation, osteoarthritis, cataracts and arterial disorders. 

Bone sialoprotein, osteopontin, and osteocalcin are synthesized and deposited as the mineralization process begins and mineral nodules form (Stein and Lian, 1993). Bone sialoprotein contains the cell-adhesive arginine-glycine-aspartic acid peptide sequence and may thus mediate osteoblast adhesion on the extracellular matrix (Gehron-Robey, 1989). Osteocalcin, a calcium-binding protein, interacts with hydroxyapatite and is thought to mediate coupling of bone resorption (by osteoclasts) and bone formation (by osteoblasts and/or osteocytes) (Stein and Lian, 1993). 

The adhesion of cells to each other is normally due to interactions that involve a number of proteins of the extracellular matrix and the plasma membrane. Cadherin is a membrane-boimd protein. The N terminus of cadherin is extracellular. The N termini of cadherins sticking out of adjacent cells bind to each other. This interaction requires calcivun ions, hence the name Cadherin. An intracellular interaction is also required for adhesion to occur between cells. The C terminus of cadherin contacts the cytosol and binds to a protein called catenin (pronounced ca-TEE-nin). Catenin, in turn, binds to the cytoskeleton. The cytoskeleton is a network of proteins that crisscross about the plasma membrane and through the cell. Defects in the cadherin gene have been found in many samples of colorectal cancer. These mutations tend to occur in the N-terminal region, i.e., in the extracellular calcium-binding domain. 

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