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Structural studies of human glioma pathogenesis‐related protein 1

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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 Zn2+ complex was refined to 2.2 Å resolution. The latter structure revealed that the putative binding cavity coordinates Zn2+ similarly to snake‐venom CRISPs, which are involved in Zn2+‐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.

Document Type: Research Article

DOI: https://doi.org/10.1107/S0907444911028198

Publication date: 2011-10-01

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