Cell Reports
Volume 8, Issue 6, 25 September 2014, Pages 1704-1713
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Structural Insights into the Tumor-Promoting Function of the MTDH-SND1 Complex

https://doi.org/10.1016/j.celrep.2014.08.033Get rights and content
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Highlights

  • Two tryptophan residues in MTDH bind to separate hydrophobic pockets in SND1

  • The MTDH-binding pockets are unique, absent in SN3/4 or other OB-fold proteins

  • Mutations at the MTDH-SND1 interface impair tumor initiation of breast cancer

  • Hydrophobic pockets in SND1 are specific targets for developing cancer therapeutics

Summary

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.

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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Present address: Stanford University, School of Medicine, Stanford, CA 94305, USA