Sandbox Reserved 427: Difference between revisions
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'''The Vitamin D Binding Site''' | '''The Vitamin D Binding Site''' | ||
The Vitamin D binding site is located in domain I and contains helices 1 through 6. The binding site is lined with hydrophobic residues that interact with the hydrophobic parts of the vitamin D3 ligand.<scene name='48/483884/Site_where_25ohd3_binds/3'>Hydrogen Bonds</scene> are formed between, the 25-hydroxyl and Tyr 32 with a distance of 2.85 angstroms, the 3-hydroxyl and Ser 76 with a distance of 3.01 angstroms and Met 109 with a distance of 3.01 angstroms.[1] Different analogs of the vitamin D3 ligand influence hydrogen bond locations and binding affinities. <scene name='48/483884/Jy_site_where_25ohd3_binds/5'>The JY analog</scene>, for example, has a binding affinity to DBP of 1314, which is much greater compared to the affinity of 25OHD3, which is 667.[1] This is due to the <scene name='48/483884/Stacking_stabilization_with_jy/3'>stacking of the aromatic sidechain of JY</scene> and the aromatic residues of Phe 24, Tyr 34, Phe 36, and Tyr 38. The JX analog switches the meta hydroxyl group on JY to para, increasing the binding affinity to 2111. By switching the hydroxyl group to the para position tighter hydrogen bonds can be formed to the Ser 28 residue stabilizing the complex.[1] | The Vitamin D binding site is located in domain I and contains helices 1 through 6. The binding site is lined with hydrophobic residues that interact with the hydrophobic parts of the vitamin D3 ligand.<scene name='48/483884/Site_where_25ohd3_binds/3'>Hydrogen Bonds</scene>(locations highlighted in yellow) are formed between, the 25-hydroxyl and Tyr 32 with a distance of 2.85 angstroms, the 3-hydroxyl and Ser 76 with a distance of 3.01 angstroms and Met 109 with a distance of 3.01 angstroms.[1] Different analogs of the vitamin D3 ligand influence hydrogen bond locations and binding affinities. <scene name='48/483884/Jy_site_where_25ohd3_binds/5'>The JY analog</scene>(yellow), for example, has a binding affinity to DBP of 1314, which is much greater compared to the affinity of 25OHD3, which is 667.[1] This is due to the <scene name='48/483884/Stacking_stabilization_with_jy/3'>stacking of the aromatic sidechain of JY</scene> and the aromatic residues of Phe 24, Tyr 34, Phe 36, and Tyr 38. The JX analog switches the meta hydroxyl group on JY to para, increasing the binding affinity to 2111. By switching the hydroxyl group to the para position tighter hydrogen bonds can be formed to the Ser 28 residue stabilizing the complex.[1] | ||
'''Biological Relevance of The Vitamin D Binding Site''' | '''Biological Relevance of The Vitamin D Binding Site''' | ||
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==Additional Features== | ==Additional Features== | ||
=====Actin Binding Interactions===== | =====Actin Binding Interactions===== | ||
Vitamin D binding protein is | The most well documented auxiliary function of Vitamin D binding protein is its ability to bind and sequester circulating actin monomers. [4] The actin interaction occur at the sites shown in <scene name='48/483884/Dbp_actin_binding_site/2'>red</scene>. While the vitamin D binding domain resides between leucine 35 and serine 49, the actin binding domain lies far away in sequence, between glycine 373 and glycine 403, the site is <scene name='48/483884/Dbp_actin_dbinding_distance/1'>much closer</scene> in the folded protein, with residues serine 42 and lysine 388 only 21.44Å apart on complementary subunits or 43.58Å apart on the same subunit. | ||
At the level of the organism, this actin binding of DBP is an important mechanism for clearing actin from necrotic or apoptotic tissue [1]. This actin binding quality serves to prevent clotting and actin toxicity, as large quantities of circulating actin have been shown to be fatal to mice. | |||
[4] Interestingly enough, DBP -/- mice are phenotypically normal and physically indistinguishable from normal mice, indicating that there may be other mechanisms and proteins involved in actin sequestration. [4] | |||
=====Immune Function and Macrophage Activation===== | |||
As the name suggests, macrophages (loosely translated from Greek as “big glutton”) are a class of white blood cells that move through the bloodstream and extracellular matrix in search of large debris and pathogens. They have been known to endocytose just about any foreign material that it does not recognize as self, including a wide range of microbes, cancer cells, and other debris. They are also important in antibody formation, as they often carry the instructions for how to destroy cells they have eaten. | |||
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DBP plays a role in macrophage activation through its conversion within immune cells to a compound called macrophage activating factor (MAF). At the site of the wound various immune cells act on DBP and deglycosylate it at several sites along the backbone. [6] This factor is important in the recruitment of macrophages to wound sites and other potential areas of infection. [6] Taking into account the above mention that DBP is important for clearing actin from wound sites, it makes logical sense that it would also be able to be easily converted to an endocrine or paracrine signal in this manner. [1] | |||
==Quiz Question 1== | ==Quiz Question 1== | ||
