D binding protein
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,
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).
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
is available commercially from Calbiochem .
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,
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.
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,
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,
Sequential binding of actin monomers to plasma
gelsolin and its inhibition by vitamin D-binding protein.
Biochem. Biophys. Res. Comm.
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,
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,
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.