Structural insights into the tumor-promoting function of the MTDH-SND1 complex.

Abstract

Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) are overexpressed and interact in diverse cancer types. The structural mechanism of their interaction remains unclear. Here, we determined the high-resolution crystal structure of MTDH-SND1 complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two SN domains (SN1/2), with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. At the opposite side of the MTDH-SND1 binding interface, SND1 possesses long protruding arms and deep surface valleys that are prone to binding with other partners. Despite the simple binding mode, interactions at both tryptophan-binding pockets are important for MTDH and SND1's roles in breast cancer and for SND1 stability under stress. Our study reveals a unique mode of interaction with SN domains that dictates cancer-promoting activity and provides a structural basis for mechanistic understanding of MTDH-SND1-mediated signaling and for exploring therapeutic targeting of this complex.

• Authors: Feng Guo, Liling Wan, Aiping Zheng, Vitali Stanevich, Yong Wei, Kenneth A Satyshur, Minhong Shen, Woojong Lee, Yibin Kang, Yongna Xing
• Journal: Cell reports (Cell Rep) Vol. 8 Issue 6 Pg. 1704-1713 (Sep 25 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 25242325 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cell Adhesion Molecules
• MTDH protein, human
• Membrane Proteins
• Nuclear Proteins
• RNA-Binding Proteins
• Recombinant Fusion Proteins
• Endonucleases
• SND1 protein, human

Topics

• Animals
• Binding Sites
• Cell Adhesion Molecules (chemistry, genetics, metabolism)
• Cell Line, Tumor
• Crystallography, X-Ray
• Endonucleases
• Humans
• Hydrogen Bonding
• Membrane Proteins
• Mice
• Molecular Dynamics Simulation
• Mutagenesis, Site-Directed
• Nuclear Proteins (chemistry, genetics, metabolism)
• Protein Binding
• Protein Structure, Tertiary
• RNA-Binding Proteins
• Recombinant Fusion Proteins (biosynthesis, chemistry, genetics)
• Static Electricity