title: 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.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Liling
authors.initials: L
authors.lastname: Wan
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zheng
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Vitali
authors.initials: V
authors.lastname: Stanevich
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wei
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Satyshur
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Minhong
authors.initials: M
authors.lastname: Shen
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Woojong
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: ykang@princeton.edu.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA. Electronic address: xing@oncology.wisc.edu.
authors.forename: Yongna
authors.initials: Y
authors.lastname: Xing
mesh_terms: D000818:Animals; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004720:Endonucleases; D006801:Humans; D006860:Hydrogen Bonding; D008565:Membrane Proteins; D051379:Mice; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D055672:Static Electricity
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D004720:Endonucleases; C095221:SND1 protein, human