Sandbox Reserved 703
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| 2v3q, resolution 1.89Å () | |||||||||
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| Ligands: | , , | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
DescriptionDescription
The human phosphate binding apoliprotein (HPBP) is a 38kDa apoliprotein, and belongs to the family of ubiquitous eukaryotic proteins named DING, an extracellular protein family including four conserved amino acids at its N-terminal end.[1][2] It is the only known transporter capable of binding phosphate ions in the human plasma. HPBP is bound to PON1, a calcium-dependent enzyme associated to HDL (High Density Lipoprotein), another lipoprotein which enables lipids like cholesterol and triglycerides to be transported from the blood to the liver. It is the place where these lipids can be removed, reducing for example the amount of arterial cholesterol. HPBP is always copurified with the enzyme paraoxonase (PON1), that is why it was always ignored before 2006. The copurification is the result of a similar molecular weight, strong hydrophobic interactions, and the fact that PON1 is a glycosylated protein. The separation of the two molecules involves a hydroxyapatite chromatography with phosphate concentration gradient elution.[3][4]
Up to now, HPBP has never been characterized or predicted from nucleic acid databases of human genome.[5] Its X-ray structure is similar to the prokaryotic phosphate solute binding proteins (SBPs) associated with ATP binding cassette transmembrane transporters. Their role is to enable the unidirectional transport of substances trough the membrane, using ATP hydrolysis.
Activity and physiological functionsActivity and physiological functions
HPBP is associated in vivo with PON1, and binds inorganic phosphate ions.[6] During research, it was possible to show that the separation of HPBP and PON1 involves a fast denaturing of the two proteins, which means that the PON1/HPBP complex is essential for each other’s stability. The different oligomeric organisations of the PON1/HPBP complex depend on the calcium, phosphate and detergent concentrations. Therefore, this complex is implicated in the phosphocalcic metabolism. Normally, the phosphate concentration should always be around 0.5-1.0 mM, hence HPBP is always saturated with phosphate. The existence of a phosphate detector in human plasma, associated with a lipoprotein, demonstrate the necessity to avoid the direct contact between phosphate and calcium. Indeed, hyperphosphatemia is a risk factor for cardio vascular diseases.[7][8]
StructureStructure
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HPBP consists of 376 residues with a predicted molecular mass of 38.4 kDa. It contains two similar global domains, connected by a . Each is constituted by a five-stranded core (three parallel β strands followed by two antiparallel β strands) flanked by . There are two disulfide bridges (, ).
The is similar to other phosphate SBPs and the surface of the binding pocket is negative. In total, 8 residues and 13 hydrogen bonds are involved in the binding of the substrate creating a rich network. 12 bonds are formed by dipolar donor groups with (T8, L9, S32, G145, T146) mostly located at the end of 3 helices, of the R140 side chain and 4 from side chains of 4 residues (T8, S32, S144, T146).
generates two hydrogen bonds with both negative oxygen atoms of the dibasic phosphate. This interaction, by diminishing the charge coupling interaction between the guanidium and phosphate, has previously been described as essential for the fast release of the ionic substrate bound with charged residues.
is the only dipolar acceptor group that makes a hydrogen bond with the only proton available on dibasic phosphate.
The negative surface of the binding pocket and the D61 of the HPBP are involved in the specificity towards the phosphate. Due to the negative environment only anions perfectly matching the hydrogen bonds are able of binding. The D61 residue is responsible for the discrimination between phosphate and the very similar sulfate, which is missing the hydrogen needed for the bond with D61. [9]
ApplicationsApplications
HPBP is the only known transporter capable of binding phosphate ions in human plasma. It may become a new predictor of or a potential therapeutic agent for phosphate-related diseases such as atherosclerosis, since it is known that a high phosphate amount is linked to cardio-vascular diseases, by inducing atheromatous plaques (lipid sediments) in arteries.
On the other hand, scientists were able to demonstrate a connexion between HPBP and HIV-1 gene transcription. The data proved that HPBP is most likely able to block HIV1-LTR (Long Terminal Repeats) promoted expression and replication, preventing the HIV1 virus to multiply. It also works on mutant HIV strains. This discovery opens up a completely new field for drug research, which could lead to an innovative HIV-treatment.[10]
External ResourcesExternal Resources
ReferencesReferences
- ↑ Collombet JM, Elias M, Gotthard G, Four E, Renault F, Joffre A, Baubichon D, Rochu D, Chabriere E. Eukaryotic DING proteins are endogenous: an immunohistological study in mouse tissues. PLoS One. 2010 Feb 8;5(2):e9099. doi: 10.1371/journal.pone.0009099. PMID:20161715 doi:10.1371/journal.pone.0009099
- ↑ Berna A, Bernier F, Scott K, Stuhlmuller B. Ring up the curtain on DING proteins. FEBS Lett. 2002 Jul 31;524(1-3):6-10. PMID:12135732
- ↑ Renault F, Chabriere E, Andrieu JP, Dublet B, Masson P, Rochu D. Tandem purification of two HDL-associated partner proteins in human plasma, paraoxonase (PON1) and phosphate binding protein (HPBP) using hydroxyapatite chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 May 19;836(1-2):15-21. Epub, 2006 Apr 3. PMID:16595195 doi:10.1016/j.jchromb.2006.03.029
- ↑ Clery-Barraud C, Renault F, Leva J, El Bakdouri N, Masson P, Rochu D. Exploring the structural and functional stabilities of different paraoxonase-1 formulations through electrophoretic mobilities and enzyme activity parameters under hydrostatic pressure. Biochim Biophys Acta. 2009 Apr;1794(4):680-8. doi: 10.1016/j.bbapap.2009.01.003. , Epub 2009 Jan 29. PMID:19336040 doi:10.1016/j.bbapap.2009.01.003
- ↑ Diemer H, Elias M, Renault F, Rochu D, Contreras-Martel C, Schaeffer C, Van Dorsselaer A, Chabriere E. Tandem use of X-ray crystallography and mass spectrometry to obtain ab initio the complete and exact amino acids sequence of HPBP, a human 38-kDa apolipoprotein. Proteins. 2008 Jun;71(4):1708-20. PMID:18076037 doi:10.1002/prot.21866
- ↑ Contreras-Martel C, Carpentier P, Morales R, Renault F, Chesne-Seck ML, Rochu D, Masson P, Fontecilla-Camps JC, Chabriere E. Crystallization and preliminary X-ray diffraction analysis of human phosphate-binding protein. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2006 Jan 1;62(Pt 1):67-9. Epub , 2005 Dec 16. PMID:16511265 doi:10.1107/S1744309105041461
- ↑ Rochu D, Renault F, Clery-Barraud C, Chabriere E, Masson P. Stability of highly purified human paraoxonase (PON1): association with human phosphate binding protein (HPBP) is essential for preserving its active conformation(s). Biochim Biophys Acta. 2007 Jul;1774(7):874-83. Epub 2007 May 22. PMID:17556053 doi:10.1016/j.bbapap.2007.05.001
- ↑ Rochu D, Chabriere E, Renault F, Elias M, Clery-Barraud C, Masson P. Stabilization of the active form(s) of human paraoxonase by human phosphate-binding protein. Biochem Soc Trans. 2007 Dec;35(Pt 6):1616-20. PMID:18031277 doi:10.1042/BST0351616
- ↑ Morales R, Berna A, Carpentier P, Contreras-Martel C, Renault F, Nicodeme M, Chesne-Seck ML, Bernier F, Dupuy J, Schaeffer C, Diemer H, Van-Dorsselaer A, Fontecilla-Camps JC, Masson P, Rochu D, Chabriere E. Serendipitous discovery and X-ray structure of a human phosphate binding apolipoprotein. Structure. 2006 Mar;14(3):601-9. PMID:16531243 doi:10.1016/j.str.2005.12.012
- ↑ Cherrier T, Elias M, Jeudy A, Gotthard G, Le Douce V, Hallay H, Masson P, Janossy A, Candolfi E, Rohr O, Chabriere E, Schwartz C. Human-Phosphate-Binding-Protein inhibits HIV-1 gene transcription and replication. Virol J. 2011 Jul 15;8:352. doi: 10.1186/1743-422X-8-352. PMID:21762475 doi:10.1186/1743-422X-8-352
ContributorsContributors
Demir Fijuljanin, Christine Ponkratz