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Ovchinnikov, Sergey

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Ovchinnikov

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Sergey

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Ovchinnikov, Sergey

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2017 - 201912020 - 20231

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Author's Publications: search.filters.isAuthorOfPublication.74dc0e04-5af2-4bde-b7fc-3bc3018a7cbc

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    Co-evolution-based prediction of metal-binding sites in proteomes by machine learning
    (Springer Science and Business Media LLC, 2023-01-02) Cheng, Yao; Wang, Haobo; Xu, Hua; Liu, Yuan; Ma, Bin; Chen, Xuemin; Zeng, Xin; Wang, Xianghe; Wang, Bo; Shiau, Carina; Ovchinnikov, Sergey; Su, Xiao-Dong; Wang, Chu
    Metal ions play various important biological role in proteins including structural maintenance, molecular recognition and catalysis. Previous methods of predicting metal-binding sites in proteomes were based on either sequence or structural motifs. Here, we developed a coevolution28 based pipeline named “MetalNet” to systematically predict metal-binding sites in proteomes. We applied MetalNet to proteomes of four representative prokaryotic species and predicted 4,849 potential metalloproteins which significantly expands the currently annotated metalloproteomes. We biochemically and structurally validated previously unannotated metal-binding sites in several proteins, including apo-citrate lyase phosphoribosyl-dephospho-CoA transferase citX, an E.coli enzyme lacking structural or sequence homology to any known metalloprotein (PDB ID: 7DCM and 7DCN). MetalNet also successfully recapitulated all known zinc-binding sites from the human spliceosome complex. The pipeline of MetalNet provides a unique and enabling tool for interrogating the hidden metalloproteome and studying metal biology.
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    Cryo-EM Structure of the Protein-Conducting ERAD Channel Hrd1 in Complex With Hrd3
    (Springer Science and Business Media LLC, 2017-07-06) Schoebel, Stefan; Mi, Wei; Stein, Alexander; Ovchinnikov, Sergey; Pavlovicz, Ryan; DiMaio, Frank; Baker, David; Chambers, Melissa G.; Su, Huayou; Li, Dongsheng; Rapoport, Tom; Liao, Maofu
    Misfolded endoplasmic reticulum proteins are retro-translocated through the membrane into the cytosol, where they are poly-ubiquitinated, extracted from the membrane, and degraded by the proteasome—a pathway termed endoplasmic reticulum-associated protein degradation (ERAD). Proteins with misfolded domains in the endoplasmic reticulum lumen or membrane are discarded through the ERAD-L and ERAD-M pathways, respectively. In Saccharomyces cerevisiae, both pathways require the ubiquitin ligase Hrd1, a multi-spanning membrane protein with a cytosolic RING finger domain. Hrd1 is the crucial membrane component for retro-translocation, but it is unclear whether it forms a protein-conducting channel. Here we present a cryo-electron microscopy structure of S. cerevisiae Hrd1 in complex with its endoplasmic reticulum luminal binding partner, Hrd3. Hrd1 forms a dimer within the membrane with one or two Hrd3 molecules associated at its luminal side. Each Hrd1 molecule has eight transmembrane segments, five of which form an aqueous cavity extending from the cytosol almost to the endoplasmic reticulum lumen, while a segment of the neighbouring Hrd1 molecule forms a lateral seal. The aqueous cavity and lateral gate are reminiscent of features of protein-conducting conduits that facilitate polypeptide movement in the opposite direction—from the cytosol into or across membranes. Our results suggest that Hrd1 forms a retro-translocation channel for the movement of misfolded polypeptides through the endoplasmic reticulum membrane.