Abstract 4746: Structural studies of human glioma pathogenesis-related protein 1(GLIPR1)

Abstract

Abstract Human glioma pathogenesis-related protein 1 (GLIPR1) is a membrane protein that is highly upregulated in brain cancers but barely detectable in normal brain tissue. GLIPR1 is composed of a signal peptide, to direct its secretion, a conserved cysteine-rich CAP (cysteine-rich secretory protein, antigen 5, pathogenesis related-1) domain, and a transmembrane domain. Phase I/II clinical trial involving direct injection of neoadjuvant GLIPR1 prior to radical prostatectomy are underway (IND #13033). GLIPR1 gene therapy has been shown to be anti-metastatic in an orthotopic mouse model of prostate cancer. GLIPR1 is also currently being investigated for glioblastoma targeted therapy. We present here crystal structures of a truncated soluble domain of the human GLIPR1 protein, sGLIPR1, solved by molecular replacement (MR) using a truncated polyalanine model of the CAP domain of stecrisp, a snake venom CRISP (cysteine-rich secretory protein), in PHASER. The correct MR solution could only be obtained by removing all loops in the search model. While, the native structure was refined to 1.85 Å, that of the Zn2+ complex was refined to 2.2 Å. The latter structure reveals 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. We also propose a model for the structure of the full-length, membrane-bound GLIPR1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4746. doi:1538-7445.AM2012-4746