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Title: Structural studies of human glioma pathogenesis-related protein 1

Structural analysis of a truncated soluble domain of human glioma pathogenesis-related protein 1, a membrane protein implicated in the proliferation of aggressive brain cancer, is presented. 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{sup 2+} complex was refined to 2.2 Å resolution. The latter structure revealed that the putative binding cavity coordinates Zn{sup 2+} similarly to snake-venom CRISPs, which are involved in Zn{sup 2+}-dependent mechanisms of inflammatory modulation. Bothmore » 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.« less
Authors:
 [1] ; ;  [2] ;  [3]
  1. College of Medicine, Nebraska Medical Center, Omaha, NE 68198-6495 (United States)
  2. L2 Diagnostics LLC, 300 George Street, New Haven, CT 06511 (United States)
  3. (United States)
Publication Date:
OSTI Identifier:
22351246
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 67; Journal Issue: Pt 10; Other Information: PMCID: PMC3176621; PMID: 21931216; PUBLISHER-ID: be5181; OAI: oai:pubmedcentral.nih.gov:3176621; Copyright (c) International Union of Crystallography 2011; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; CHARGE DISTRIBUTION; CRYSTAL STRUCTURE; CYSTEINE; DISTRIBUTION; LENGTH; MATHEMATICAL SOLUTIONS; MEMBRANES; MODULATION; PROLIFERATION; PROTEIN STRUCTURE; RESOLUTION; SIGNALS; SOLUTIONS