Structural studies of human glioma pathogenesis-related protein 1

Abstract

Human glioma pathogenesis-related protein 1 (GLIPR1) is a membrane protein that is highly upregulated in brain cancers but is barely detectable in normal brain tissue. GLIPR1 is composed of a signal peptide that directs its secretion, a conserved cysteine-rich CAP (cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 proteins) domain and a transmembrane domain. GLIPR1 is currently being investigated as a candidate for prostate cancer gene therapy and for glioblastoma targeted therapy. Crystal structures of a truncated soluble domain of the human GLIPR1 protein (sGLIPR1) solved by molecular replacement using a truncated polyalanine search model of the CAP domain of stecrisp, a snake-venom cysteine-rich secretory protein (CRISP), are presented. The correct molecular-replacement solution could only be obtained by removing all loops from the search model. The native structure was refined to 1.85 Å resolution and that of a Zn 2+ complex was refined to 2.2 Å resolution. The latter structure revealed that the putative binding cavity coordinates Zn 2+ similarly to snake-venom CRISPs, which are involved in Zn 2+ -dependent mechanisms of inflammatory modulation. Both sGLIPR1 structures have extensive flexible loop/turn regions and unique charge distributions that were not observed in any of the previously reported CAP protein structures. A model is also proposed for the structure of full-length membrane-bound GLIPR1.

Genomic profiling of invasive melanoma cell lines by array comparative genomic hybridization

“…According to previous studies, after the translocation of the GLIPR1 (GLI pathogenesis-related 1) protein to the cell surface, the soluble N-terminal domain of the molecule is exposed to the extracellular space, which can lead to invasion [48,49]. In the present study, gain of the GLIPR1 gene was observed specifically in invasive cell lines.…”

Variable Expression of GLIPR1 Correlates with Invasive Potential in Melanoma Cells

“…We confirm that it is a glycoprotein, most likely at the predicted glycosylation site at asparagine 92 (5), which is shown by homology modeling of GLIPR1 to be on the surface of the protein (data not shown). Glycosylation was also seen in the recent expression and structural studies by Asojo and co-workers (23, 24). GLIPR1 is translocated to the cell surface where its soluble N-terminal domain will be exposed to the extracellular space.…”

A dimeric PR‐1‐type pathogenesis‐related protein interacts with ToxA and potentially mediates ToxA‐induced necrosis in sensitive wheat

“…Homology-based modelling for the cone snail (Conus textile) Tex31 (Milne et al, 2003) and human GAPR-1 (Serrano et al, 2004) proteins suggested a 'catalytic triad' consisting of serine (Ser)-73 with Glu-98/His-117 (or Glu-77/His-72) within the largest cavity in the PR-1 fold, which is reminiscent of that of serine proteases, but none of these PR-1like proteins has been confirmed to possess protease activity. Recent studies in human/animal systems have suggested 'novel' functions for PR-1-like proteins based on several newly identified properties, including coordination with divalent metal ions, such as Zn 2+ (Asojo et al, 2011;Wang et al, 2010), and binding to negatively charged membrane-associated lipids (van Galen et al, 2012) or certain fatty acid-derived lipid signalling molecules, such as leukotrienes (Xu et al, 2012). The importance of these unusual features in specific physiological processes has not been well established.…”