Serendipitous Discovery and X-Ray Structure of a Human Phosphate Binding Apolipoprotein

Laboratoire de Cristallogenèse et Cristallographie des Protéines, Institut de Biologie Structurale JP EBEL, 38027 Grenoble, France.
Structure (Impact Factor: 6.79). 04/2006; 14(3):601-9. DOI: 10.1016/j.str.2005.12.012
Source: PubMed

ABSTRACT We report the serendipitous discovery of a human plasma phosphate binding protein (HPBP). This 38 kDa protein is copurified with the enzyme paraoxonase. Its X-ray structure is similar to the prokaryotic phosphate solute binding proteins (SBPs) associated with ATP binding cassette transmembrane transporters, though phosphate-SBPs have never been characterized or predicted from nucleic acid databases in eukaryotes. However, HPBP belongs to the family of ubiquitous eukaryotic proteins named DING, meaning that phosphate-SBPs are also widespread in eukaryotes. The systematic absence of complete genes for eukaryotic phosphate-SBP from databases is intriguing, but the astonishing 90% sequence conservation between genes belonging to evolutionary distant species suggests that the corresponding proteins play an important function. HPBP is the only known transporter capable of binding phosphate ions in human plasma and may become a new predictor of or a potential therapeutic agent for phosphate-related diseases such as atherosclerosis.

Download full-text


Available from: Carlos Contreras-Martel, Jul 04, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: DING proteins comprise an intriguing phosphate-binding protein family present in all animal phyla. Five different DING representatives have been described in humans. Eukaryotic DING proteins are mostly involved in cellular processes such as cell cycle regulation, and also in pathological process such as rheumatoid arthritis and kidney stone formation. Although these proteins are ubiquitous in eukaryotes, no relevant locus or ORF has yet been found in sequenced genomes. This lack of sequence information has considerably hampered functional and structural studies of these proteins, and has required the use of novel and original techniques such as ab initio protein sequencing based on a combination of X-ray crystallography and mass spectrometry. Sub-Angstrom structural resolution has elucidated the molecular binding mechanism of phosphate ions by these high-affinity proteins. Immunohistochemical studies show that these proteins are present in a wide variety of mouse tissues. Some DING proteins, particularly human phosphate binding protein (HPBP), can inhibit HIV replication. This inhibition takes place at the transcriptional step, which is not targeted by any current antiretroviral drug. Initial studies suggest that HPBP warrants animal testing. This recent discovery opens new possibilities for the treatment of HIV infection.
    Bulletin de l'Académie nationale de médecine 03/2012; 196(3):693-703; discussion 704. · 0.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ethanol induces neuronal cell injury and death by dysregulating several signaling events that are controlled, in part, by activation of MAPK/ERK1/2 and/or inactivation of its corresponding phosphatase, PP1. Recently, we have purified a novel protein of 38 kDa in size, p38SJ, from a callus culture of Hypericum perforatum, which belongs to an emerging DINGG family of proteins with phosphate binding activity. Here, we show that treatment of neuronal cells with p38SJ protects cells against injury induced by exposure to ethanol. Furthermore, pre-treatment of neuronal cells with p38SJ diminishes the level of the pro-apoptotic protein Bax and some events associated with apoptosis such as caspase 3 cleavage. In addition, by inducing stress, alcohol can elevate production of reactive oxygen species (ROS) that leads to a decrease in the activity of superoxide dismutase (SOD). Our results showed that p38SJ restores the activity of SOD in the ethanol treated neuronal cells. These observations provide a novel biological tool for developing new approaches for preventing neuronal cell death induced by ethanol and possibly treatment of neurological disorders associated with alcohol abuse.
    Journal of Cellular Physiology 12/2009; 221(3):499-504. DOI:10.1002/jcp.21903 · 3.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We reported previously the anti-viral activity named HRF (HIV-1 Resistance Factor) secreted by HIV-1 resistant cells. This work describes the identification of HRF from cell culture supernatant of HRF-producing cells (HRF(+) cells). Employing the proteomics and cell based activity assay we recovered ten peptides sharing 80-93% sequence homology with other eukaryotic DING proteins; discrete amino acid characteristics found in our material suggested that HRF is a new member of DING proteins family and consequently we designated it as X-DING-CD4 (extracellular DING from CD4(+) T cells). The presence of X-DING-CD4 in the extracellular compartment of HRF(+) but not control HRF(-) cells was confirmed by specific anti-X-DING-CD4 antibody. Similar as the un-fractionated HRF(+) cell culture supernatant, the purified X-DING-CD4 blocked transcription of HIV-1 LTR-promoted expression of luciferase gene and replication of HIV-1 in MAGI cells. The X-DING-CD4 -mediated anti-viral activity in MAGI cells could be blocked by specific antibody.
    Biochemical and Biophysical Research Communications 09/2009; 389(2):284-9. DOI:10.1016/j.bbrc.2009.08.140 · 2.28 Impact Factor