Abstract
Independent research groups reported that DING protein homologues isolated from bacterial, plant and human cells demonstrate the anti-HIV-1 activity. This might indicate that diverse organisms utilize a DING-mediated broad-range protective innate immunity response to pathogen invasion, and that this mechanism is effective also against HIV-1. We performed structural analyses and evaluated the anti-HIV-1 activity for four DING protein homologues isolated from different species. Our data show that bacterial PfluDING, plant p38SJ (pDING), human phosphate binding protein (HPBP) and human extracellular DING from CD4 T cells (X-DING-CD4) share high degrees of structure and sequence homology. According to earlier reports on the anti-HIV-1 activity of pDING and X-DING-CD4, other members of this protein family from bacteria and humans were able to block transcription of HIV-1 and replication of virus in cell based assays. The efficacy studies for DING-mediated HIV-1 LTR and HIV-1 replication blocking activity showed that the LTR transcription inhibitory concentration 50 (IC50) values ranged from 0.052–0.449 ng/ml; and the HIV-1 replication IC50 values ranged from 0.075–0.311 ng/ml. Treatment of cells with DING protein alters the interaction between p65-NF-κB and HIV-1 LTR. Our data suggest that DING proteins may be part of an innate immunity defense against pathogen invasion; the conserved structure and activity makes them appealing candidates for development of a novel therapeutics targeting HIV-1 transcription.
Highlights
DING proteins were recently clustered into a new group of highly conserved proteins found in prokaryotes and eukaryotes throughout the plant and animal kingdoms [1,2,3,4,5,6,7]
The only existing crystal structures of DING proteins were derived from the human phosphate binding protein (HPBP) [10] and the bacterial PfluDING [11]
We showed that X-DING-CD4 was the most potent inhibitor of HIV-1 transcription and replication, followed by HPBP and pDING approximately at the same level and by PfluDING
Summary
DING proteins were recently clustered into a new group of highly conserved proteins found in prokaryotes and eukaryotes throughout the plant and animal kingdoms [1,2,3,4,5,6,7]. The DING proteins belong to the superfamily of phosphate-binding proteins (PBP) which comprises PstS and alkaline phosphatase (AP), both exclusively found in prokaryotes [8]. The structural differences on four external loops and presence of two disulfide bridges in DINGs stand them apart from other PBPs and suggest an autonomous class of proteins [12]. The phosphate molecule in the DING protein resides in the vicinity of the binding cleft formed by the two globular domains. The binding of this phosphate ion occurs between four conserved residues in each globular domain, that form a complex network of 12 hydrogen bonds [11]. It has been shown that presence of an aspartic acid (D62) in this phosphate-binding pocket is important for the distinction between the phosphate and other closely-related ions such as sulfate or arsenate [13,14]
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