Ligand binding reveals a role for heme in translationally-controlled tumor protein dimerization

• Published in: PloS one 2014-11, Vol.9 (11), p.e112823-e112823
• Main Authors: Lucas, Andrew T, Fu, Xiangping, Liu, JingJing, Brannon, Mary K, Yang, Jianhua, Capelluto, Daniel G S, Finkielstein, Carla V
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs - genetics; Amino Acid Sequence; Apoptosis; Binding; Biology and Life Sciences; Biomarkers, Tumor - chemistry; Biomarkers, Tumor - metabolism; Buffers; Calcium; Calcium - metabolism; Cell cycle; Cell death; Cell growth; Cellular signal transduction; Chemical properties; Chromatography, High Pressure Liquid; Circular Dichroism; Computational Biology; Cross-Linking Reagents; Dimerization; Electrophoresis, Polyacrylamide Gel; Eukaryotes; Fluorescence; Genetic transformation; Heme; Hemin; Hemin - metabolism; Homeostasis; Homeostasis - genetics; Homeostasis - physiology; Humans; Kinases; Ligands; Molecular Sequence Data; Mutation; Nuclear Magnetic Resonance, Biomolecular; Oligomerization; Oligomers; Parasites; Protein Binding; Protein Biosynthesis - physiology; Protein Conformation; Rodents; Sequence Alignment; Transduction; Transformation; Transformations (mathematics); Tumors; Ultracentrifugation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0112823

The translationally-controlled tumor protein (TCTP) is a highly conserved, ubiquitously expressed, abundant protein that is broadly distributed among eukaryotes. Its biological function spans numerous cellular processes ranging from regulation of the cell cycle and microtubule stabilization to cell growth, transformation, and death processes. In this work, we propose a new function for TCTP as a "buffer protein" controlling cellular homeostasis. We demonstrate that binding of hemin to TCTP is mediated by a conserved His-containing motif (His76His77) followed by dimerization, an event that involves ligand-mediated conformational changes and that is necessary to trigger TCTP's cytokine-like activity. Mutation in both His residues to Ala prevents hemin from binding and abrogates oligomerization, suggesting that the ligand site localizes at the interface of the oligomer. Unlike heme, binding of Ca2+ ligand to TCTP does not alter its monomeric state; although, Ca2+ is able to destabilize an existing TCTP dimer created by hemin addition. In agreement with TCTP's proposed buffer function, ligand binding occurs at high concentration, allowing the "buffer" condition to be dissociated from TCTP's role as a component of signal transduction mechanisms.