Structure of human guanylate-binding protein 1 representing a unique class of GTP-binding proteins

Abstract

Interferon-gamma is an immunomodulatory substance that induces the expression of many genes to orchestrate a cellular response and establish the antiviral state of the cell. Among the most abundant antiviral proteins induced by interferon-gamma are guanylate-binding proteins such as GBP1 and GBP2. These are large GTP-binding proteins of relative molecular mass 67,000 with a high-turnover GTPase activity and an antiviral effect. Here we have determined the crystal structure of full-length human GBP1 to 1.8 A resolution. The amino-terminal 278 residues constitute a modified G domain with a number of insertions compared to the canonical Ras structure, and the carboxy-terminal part is an extended helical domain with unique features. From the structure and biochemical experiments reported here, GBP1 appears to belong to the group of large GTP-binding proteins that includes Mx and dynamin, the common property of which is the ability to undergo oligomerization with a high concentration-dependent GTPase activity.

Intra- and Intermolecular Domain Interactions of the C-terminal GTPase Effector Domain of the Multimeric Dynamin-like GTPase Drp1

“…The interdomain interactions of Drp1 could be predicted based upon results of the guanylate-binding protein 1 crystal structure and structural studies of the related dynamin and Mx proteins (18,(21)(22)(23). However, to date results for Drp1/Dnm1p results have been inconclusive.…”

“…In dynamin, dimers/tetramers assemble to form rings and collars at the base of clathrin-coated pits, inducing cooperative increases in its GTPase activity (2)(3)(4)(5). Formation of higher order structures and cooperative increases in GTPase activity have also been described for the dynamin-related Mx and guanylate-binding protein families (17)(18)(19)(20). In many cases, detailed analyses have been performed to characterize the domains involved in assembly and cooperative GTPase stimulation of these proteins.…”

“…Most appear to have an N-terminal GTP-binding domain, a middle assembly domain, a short insert (in dynamin, a pleckstrin homology domain), and a C-terminal assembly domain dubbed the "GTPase effector domain" (GED). 1 In the case of the dynamin, guanylate-binding protein, and Mx proteins, an intramolecular domain association has been identified, with the GED domain folding back to interact with the GTP-middle domains (18,(21)(22)(23). The GED domain is critical for not only assembly of higher order complexes but also for cooperative stimulation of GTPase activity.…”

Guanylate-Binding Protein-1 Expression Is Selectively Induced by Inflammatory Cytokines and Is an Activation Marker of Endothelial Cells during Inflammatory Diseases

“…[17][18][19] In particular, based on the crystal structure of GBP-1 20,21 and on biochemical considerations, it was proposed that GBP-1 belongs to the group of large GTP-binding proteins such as Mx and dynamin, all of which have a similar domain composition and GTPase activity, although sequence homology is very low. 20 We have shown that GBP-1 is the key and selective mediator of the anti-proliferative effect of ICs on both microvascular and macrovascular endothelial cells in vitro and that GBP-1 expression was inversely related with cell proliferation in vessel endothelial cells of Kaposi's sarcoma (KS) in vivo. In addition, GBP-1 expression in endothelial cells was found to be highly induced by ICs and inhibited by angiogenic growth factors.…”

Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN-γ-inducible cofactor

“…G uanylate-binding proteins (GBPs) belong to a family of large GTPases that includes dynamins and Mx proteins (1,2). These proteins are characterized by their ability to oligomerize and can display oligomerization-dependent stimulation of GTP hydrolysis (3).…”