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Instruments / Technical Area	Publication Details	Published	Actions
I24-Microfocus Macromolecular Crystallography	iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition Shuo Chen , Jiale Wu , Shan Zhong , Yuntong Li , Ping Zhang , Jingyi Ma , Jingshan Ren , Yun Tan , Yunhao Wang , Kin Fai Au , Christian Siebold , Gareth L. Bond , Zhu Chen , Min Lu , E. Yvonne Jones , Xin Lu Proceedings Of The National Academy Of Sciences 175 DOI: 10.1073/pnas.1909393116 Open Access Show Abstract ▼ Abstract: The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53–iASPP crystal structure reveals that iASPP displaces the p53 L1 loop—which mediates sequence-specific interactions with the signature-corresponding base—without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF–DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain—except the oncogenic E6 from human papillomaviruses (HPVs)—structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.	Aug 2019
I24-Microfocus Macromolecular Crystallography	Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. Shuo Chen , Doryen Bubeck , Bryan T Macdonald , Wen-xue Liang , Jian-hua Mao , Tomas Malinauskas , Oscar Llorca , Alexandru Aricescu , Christian Siebold , Xi He , Edith Jones Developmental Cell 21, 848 - 861 DOI: 10.1016/j.devcel.2011.09.007 PMID: 3564486 Show Abstract ▼ Abstract: LDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem β-propeller–EGF-like domain (PE) pairs which harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkk1). To understand how these multiple interactions are integrated, we combined crystallographic analysis of the third and fourth PE pairs with electron microscopy (EM) to determine the complete ectodomain structure. An extensive inter-pair interface, conserved for the first-to-second and third-to-fourth PE interactions, contributes to a compact platform-like architecture, which is disrupted by mutations implicated in developmental diseases. EM reconstruction of the LRP6 platform bound to chaperone Mesd exemplifies a binding mode spanning PE pairs. Cellular and binding assays identify overlapping Wnt3a- and Dkk1-binding surfaces on the third PE pair, consistent with steric competition, but also suggest a model in which the platform structure supports an interplay of ligands through multiple interaction sites.	Dec 2011

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