Crystal Structure of Prostate Secretory Protein P5P94 Shows an Edge-to-Edge Association of two Monomers to Form a Homodimer
JOURNAL OF MOLECULAR BIOLOGY
Authors: Kumar, Ashwani; Jagtap, Dhanashree D.; Mahale, Smita D.; Kumar, Mukesh
Abstract
Several recent genome-wide association studies have linked the human MSMB gene, encoding prostate secretory protein of 94 residues (P5P94), with prostate cancer susceptibility. PSP94 is one of the most abundant proteins from prostatic secretions and a primary constituent of human semen. P5P94 suppresses tumor growth and metastasis, and its expression gradually decreases during progression of the prostate cancer. It is a rapidly evolving protein with homologues present in several species with 10 conserved cysteine residues. PSP94 homologues show high-affinity binding with different proteins from the cysteine-rich secretory protein family, some of which have been shown to be ion channel blockers. Here, we report the crystal structure of human PSP94 at 2.3 angstrom resolution. The structure shows that the amino and the carboxyl ends of the polypeptide chain are held in close proximity facing each other. A strong hydrogen bond between these ends, which are located respectively on the first and the last beta-strands, leads to formation of an almost straight edge in PSP94 structure. Crystal structure shows that these edges from two P5P94 monomers associate in antiparallel fashion, leading to formation of a dimer. Our studies further show that dimers dissociate into monomers at acidic pH, possibly through distortion of the straight edge. Further, based on several observations, we propose that PSP94 binds to cysteine-rich secretory proteins and immunoglobulin G through the same edge, which is involved in the formation of P5P94 dimeric interface. (C) 2010 Elsevier Ltd. All rights reserved.
Search for genetic factor association with cancer-free prostate-specific antigen level elevation on the basis of a genome-wide association study in the Korean population
EUROPEAN JOURNAL OF CANCER PREVENTION
Authors: Choe, Eun Kyung; Lee, Young; Cho, Jeong Yeon; Choi, Seung Ho; Park, Boram; Lee, Jong-Eun; Cho, Eun Young
Abstract
We investigated the genetic markers associated with elevated serum prostate-specific antigen (sPSA) levels to improve the predictive power of sPSA in screening for prostate cancer. A genome-wide association study was carried out among 4124 healthy Korean male adults using the Affymetrix Axiom Customized Biobank Genotyping Arrays for sPSA levels. A subgroup analysis for increased sPSA levels who underwent a prostate biopsy (n=64) was also carried out. We detected 11 single nucleotide polymorphisms (SNPs) near the Solute carrier family 45member 3, AGAP7P, MSMB, LOC101929917, and KLK3 genes associated with sPSA levels. The top SNP associated with the log of the sPSA levels was rs72434280 in the Solute carrier family 45 member 3 gene (P value, discovery set=2.98x10(-20), replication set=7.31x10(-10)). A case-control study utilizing available biopsy reports (49 patients with normal biopsies vs. 15 patients with biopsies indicating cancer) for the sPSA more than 3ng/ml group was carried out for the respective SNPs after adjusting for age. Only the SNPs near the KLK3 gene were associated with prostate cancer. In the model of the predictive elevation of sPSA level, adding the genetic risk score [area under the curve (AUC)=0.697] to age and BMI (AUC=0.602) significantly improved the results of the AUC (P<0.0001). We found seven SNPs associated with elevated prostate-specific antigen levels in healthy Korean men. Four SNPs were a novel marker in the Korean population. In men with increased prostate-specific antigen levels, genotyping SNP related to cancer-free elevation of sPSA level could be informative to decide the indication of prostate biopsy.