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Vitamin D binding protein

Page updated 12/6/02

Also known as group specific protein (Gc), vitamin D binding protein (VDBP) is a 52Kda protein that binds monomeric actin in addition to vitamin D. The protein is 458 residues in length (Cooke, 1986), and forms three domains, the first of which contains the sterol binding site.  The three domains share limited sequence homology, with each other and to similar repeats in human serum albumin (HSA).  The structure of VDBP is also similar overall to HSA (Otterbein et al, 2002; Head et al, 2002).  It is presumed that the function of VDBP binding actin is to clear up any actin that enters the blood stream as a result of cell injury especially crush injury to muscle.  This function is also performed by gelsolin.  The affinity for actin monomers is high (Kd = 10-9M) (McLeod et al, 1989), and the actin binding site has been reported to reside within domain III between residues 350 and 403 (Haddad et al, 1992), although the recent structural data of the complex shows that the interface is more extensive than this and involves residues from all three domains (Otterbein et al, 2002;Head et al, 2002) .  The determination of the structure of the protein (Verboven et al, 2002) confirms the domain structure derived from the biochemical work. The structure of the complex of VDBP and actin (Otterbein et al, 2002; Head et al, 2002) confirms that domain III forms an actin-binding contact, between sub-domains 1 and 3 of actin.  However the extensive interface involves five distinct peptides from each of the three domains (Otterbein et al, 2002;Head et al, 2002).  Profilin (McLeod et al, 1989;Goldschmidt-Clermont et al, 1986) and gelsolin compete for the VDBP binding site on G-actin, whereas DNase1 does not (Goldschmidt-Clermont et al, 1985).  By comparing the structure of free VDBP and VDBP:actin complex, it is argued there is only limited conformational change in VBDP upon binding actin (Otterbein et al, 2002).

VDBP is available commercially from Calbiochem .

 

References:-

Cooke, N. E. (1986) Rat vitamin D binding protein. Determination of the full-length primary structure form cloned cDNA. J. Biol. Chem. 261, 3441-3450.

Dueland, S., Nenseter, M. S. & Drevon, C. A. (1991) Uptake and degradation of filamentous actin and vitamin D-binding protein in the rat. Biochem. J. 274, 237-241.

Goldschmidt-Clermont, P. J., Galbraith, R. M., Emerson, D. L., Marsot, F., Nel, A. E. & Arnaud, P. (1985) Distinct sites on the G-actin molecule bind group-specific component and deoxyribonuclease-I. Biochemical Journal. 228, 471-477.

Goldschmidt-Clermont, P. J., Van Alstyne, E. L., Day, J. R., Emerson, D. L., Nel, A. E., lazarchick, J. & Galbraith, R. M. (1986) Group-specific component (vitamin-d binding-protein) prevents the interaction between G-actin and profilin. Biochemistry. 25, 6467-6472.

Haddad, J. G., Hu, Y. Z., Kowalski, M. A., Laramore, C., Ray, K., Robzyk, P. & Cooke, N. E. (1992) Identification of the sterol- and actin-binding domains of plasma vitamin D binding protein (Gc-Globulin), Biochemistry. 31, 7174-7181.

Head, J. F., Swamy, N. & Ray, R. (2002) Crystal structure of the complex between actin and human vitamin D-binding protein at 2.5A resolution., Biochemistry. 41, 9015-9020.

Janmey, P. A., Stossel, T. P. & Lind, S. E. (1986) Sequential binding of actin monomers to plasma gelsolin and its inhibition by vitamin D-binding protein. Biochem. Biophys. Res. Comm. 136, 72-79.

Kew, R. R., Sibug, M. A., Liuzzo, J. P. & Webster, R. O. (1993) Localization and quantitation of the Vitamin D Binding Protein (Gc-Globulin) in Human neutrophils. Blood. 82, 274-283.

McLeod, J. F., Kowalski, M. A. & Haddad, J. G. (1989) Interactions among serum vitamin-D binding protein, monomeric actin, profilin, and profilactin. J. Biol. Chem. 264, 1260-1267.

Meijerman, I., Blom, W. M., de Bont, H., Mulder, G. J. & Nagelkerke, J. F. (1999) Changes of G-actin localisation in the mitotic spindle region or nucleus during mitosis and after heat shock: a histochemical study of G-actin in various cell lines with fluorescent labelled vitamin D-binding protein, Biochimica Et Biophysica Acta-Molecular Cell Research. 1452, 12-24.

Otterbein, L. R., Cosio, C., Graceffa, P. & Dominguez, R. (2002) Crystal structures of the vitamin D-binding protein and its complex with actin: Structural basis of the actin-scavenger system. PNAS. 99, 8003-8008.

Sabbatini, A., Petrini, M., Mattii, L., Arnaud, P. & Galbraith, R. M. (1993) Vitamin D binding protien is produced by human monocytes, FEBS letters. 323, 89-92.

Sanger, J. M., Mittal, B., Southwick, F. S. & Sanger, J. W. (1995) Listeria monocytogenes intracellular migration: inhibition by profilin, vitamin D-binding protein and DNase I. Cell Mot.Cytoskel. 30, 38-49.

Swamy, N., Head, J. F., Weitz, D. & Ray, R. (2002) Biochemical and preliminary crystallographic characterization of the vitamin D sterol- and actin-binding by human vitamin D-binding protein. Arch.Biochem.Biophy. 402, 14-23.

Verboven, C., Rabijns, A., De Maeyer, M., Van Baelen, H., Bouillon, R. & De Ranter, C. (2002) A structural basis for the unique binding features of the human vitamin D- binding protein. Nature Struct. Biol. 9, 131-136.

 
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