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.
Highlights
MTDH, known as metadherin, is overexpressed in a large spectrum of cancer types, and its elevated levels are associated with poor prognosis in cancer patients (Sarkar and Fisher, 2013; Wan and Kang, 2013)
We determined the high-resolution crystal structure of MTDH-Staphylococcal nuclease domain containing 1 (SND1) complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two Staphylococcal nuclease (SN) domains (SN1/2), with two MTDH tryptophan residues nestled into two welldefined pockets in SND1
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
Summary
MTDH, known as metadherin, is overexpressed in a large spectrum of cancer types, and its elevated levels are associated with poor prognosis in cancer patients (Sarkar and Fisher, 2013; Wan and Kang, 2013). No functional domain has been identified in the MTDH sequence, and it interacts via its unstructured regions with diverse partners, including PLZF (Thirkettle et al, 2009), NF-kB (Sarkar et al, 2008), BCCIPa (Ash et al, 2008), and SND1 (Blanco et al, 2011; Meng et al, 2012; Yoo et al, 2011). SND1 possesses tumor-promoting function similar to that of MTDH (Blanco et al, 2011; Meng et al, 2012; Wang et al, 2012; Yoo et al, 2011)
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