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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.

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    • "La capacité des protéines DING à fixer le phosphate a été clairement démontrée [6] [31], mais les liens entre cette capacité et les propriétés biologiques des protéines DING restent encore méconnus, même s'il semble que l'activité phosphatase de p27 sj et ses conséquences sur le cycle cellulaire y sont probablement liées [23]. L'affinité pour le phosphate de PfluDING et de HPBP a été évaluée respectivement à environ 1 μM [20] et à une valeur sub-micromolaire [6], des affinités similaires à celles des phosphate-SBP bactériennes [30] [32]. "
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    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
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    • "In humans, a peptide containing DINGG was first identified in synovial fluid and was found to be part of a larger protein known as p205 synovial T-cell stimulating protein (Blass et al, 1999; Hain et al, 1996). Subsequent studies led to the identification of another member of the human DINGG family with growth-promoting effects in normal and tumor cells (Adams et al, 2002; Belenky et al, 2003; Morales et al, 2006). In addition to human tissue, DINGG proteins have been isolated from various fungi, animal and plant tissues, and exhibit close homology with Pseudomonas proteins (for review see Ahn et al, 2007; Berna et al, 2002, 2008; Chen et al, 2007; Lewis and Crowther, 2005; Moniot et al, 2007; Pantazaki et al, 2007; Riah et al, 2000; Scott and Wu, 2005). "
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    Journal of Cellular Physiology 12/2009; 221(3):499-504. DOI:10.1002/jcp.21903 · 3.87 Impact Factor
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    • "A review of biological functions of DING proteins as a group revealed wide array of their activities such as neuronal [12] and skeletal muscle cell signaling [13], lymphocyte proliferation [1], or blocking adhesion of crystals to renal epithelial cells [14]. The X-ray structure of another DING member, a human plasma phosphate binding protein (HPBP), revealed its strong similarity to prokaryotic phosphate solute binding proteins (SBPs) and suggested potential role in transport of phosphate ions in human plasma [4]. "
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    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.
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