GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa)

	A schematic representation of the domain structure and the three-dimensional structure of GBP-1. GBP-1 consists of a globular domain (residues 1 to 278), which contains the GTP binding and hydrolysis domains, and of a helical domain (residues 279 to 593) terminated by a polybasic sequence and an isoprenylation motif (CAAX). C= Cysteine, A= aliphatic acid, X= any amino-acid (here a serine, specifically recognized by a farnesyl-transferase).
Description	GBP-1 belongs to the class of large GTPases that contains, in addition to the GBPs, three further groups of proteins, which share structural and biochemical properties: the dynamins, the Mx proteins and the atlastins. GBP-1 has a molecular weight of 67 kDa and its crystal structure has revealed the presence of two domains: (1) a N-terminal globular alpha/beta domain harbouring the GTPase activity and (2) a long C-terminal part organized in an index finger-like domain composed exclusively of seven alpha-helices (alpha7 - alpha13). The domains are connected by a short intermediate region consisting of one alpha-helix and a short two-stranded beta-sheet. In addition, GBP-1 harbours a C-terminal CAAX isoprenylation motif. GTPases typically harbour three classical GTP-binding domains: the phosphate-binding P-loop GXXXXGK(S/T), the phosphate- and Mg2+-binding DXXG motif (G, glycine; K, lysine; S, serine; D, aspartic acid; T, threonine; and X, any amino acid) and the guanine nucleotide-specificity providing (N/T)KXD motif (N, asparagine). In GBP-1 the classical (N/T)KXD motif is substituted by a conserved arginine-aspartic acid (RD)-motif (TLRD, with L, leucine and R, arginine).
Expression	GBP-1 was initially shown to be among the most highly induced proteins in human fibroblasts exposed to interferon (IFN)-gamma. Subsequently, it was reported that in vitro hGBP-1 expression can be induced by IFN-gamma in many different cell types including endothelial cells, fibroblasts, keratinocytes, B-cells, T-cells or peripheral blood mononuclear cells. In vivo expression of hGBP-1 has been predominantly detected in inflammatory tissues and has been found to be associated almost exclusively with endothelial cells and monocytes. It has been shown subsequently that hGBP-1 expression in endothelial cells is also induced by other pro-inflammatory cytokines such as IFNalpha, TNFalpha and IL1alpha/IL1beta. Many other cytokines (IL-4, IL-6, IL-10, IL-18), chemokines (MCP-1, PF4) or growth factors (angiopoietin-2, PDGF B/B) tested did not affect GBP-1 expression in these cells. Interestingly, the two major angiogenic growth factors (AGF: bFGF, VEGF) are able to inhibit the expression of GBP-1 induced by inflammatory cytokines.
Localisation	The localization of GBP-1 is primarily cytosolic and its distribution is granular. Plasma membrane association at the level of tight junctions has also been described. In addition, GBP-1 has been shown to be secreted from IFN-gamma-stimulated endothelial cells through a non-classical secretion pathway.
Function	GTPase activity GBP-1 can bind the three nucleotides GTP, GDP and GMP with a relative low affinity (Kd mant-GMP=0,53 μM, Kd mant-GDP=2,4 μM, Kdmant-GppNHp=1,1 μM). GBP-1 has however the ability to hydrolyse GTP to both GDP and GMP with a high hydrolysis rate (max 95 min-1). At physiological temperature GMP is the major product (90%) of hGBP1. On the contrary to small GTPases like Ras, GBP-1 does not require the presence of GEF (GTP exchange factor) or GAP (GTPase activating protein) proteins for its GTPase activity. In the case of GBP-1, the GTP hydrolysis is self-stimulated by oligomerization of the protein. GBP-1 is involved in IFN-gamma response, either in infection or in inflammation.
Homology	The human GBP family comprises 7 highly homologous members, all located on the chromosome 1. GBP-1 is to 77% similar to GBP-2, 88% to GBP-3, 56% to GBP-4, 68% to GBP-5, 54% to GBP-6 and 56% to GBP-7. Homologues have been found in various species like zebrafish, chimpanzee (99% homology), rat, dog or mouse. GBP-1 shares 59% of homology with murine GBP-1 and murine GBP-2.

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