Yu‐Hong Han

Xian Central Hospital

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Daniel R. Dries

Chapman University

Cheng‐Wu Chi

Chinese Academy of Sciences

Gang Yu

The University of Texas Southwestern Medical Center

Cong Yu

University of Science and Technology of China

Mark S. Shearman

Editas Medicine (United States)

Sanjiv Shah

Merck & Co., Inc., Rahway, NJ, USA (United States)

Sophie Yu

Merck & Co., Inc., Rahway, NJ, USA (United States)

Xiao‐Xia Shao

Tongji University

Wei‐Hai Fang

Beijing Normal University

Shari G. Birnbaum

Southwestern Medical Center

Cooperative Institutions

The University of Texas Southwestern Medical Center

Southwestern Medical Center

Tongji University

Xian Central Hospital

Chinese Academy of Sciences

Shanghai Jiao Tong University

Center for Excellence in Molecular Cell Science

Shanghai Institutes for Biological Sciences

Shanghai Sixth People's Hospital

Beijing Normal University

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Characterization of novel M‐superfamily conotoxins with new disulfide linkage

FEBS Journal (2006)

Yu‐Hong Han Qi Wang Hui Jiang Li Liu Cai Xiao

The M‐superfamily with the typical Cys framework (–CC–C–C–CC–) is one of the seven major superfamilies of conotoxins found in the venom of cone snails. Based on the number of residues in the last Cys loop (between C4 and C5), M‐superfamily conotoxins can be provisionally categorized into four branches (M‐1, M‐2, M‐3, M‐4) [Corpuz GP, Jacobsen RB, Jimenez EC, Watkins M, Walker C, Colledge C, Garrett JE, McDougal O, Li W, Gray WR, et al. (2005) Biochemistry 44 , 8176–8186]. Here we report the purification of seven M‐superfamily conotoxins from Conus marmoreus (five are novel and two are known as mr3a and mr3b) and one known M‐1 toxin tx3a from Conus textile . In addition, six novel cDNA sequences of M‐superfamily conotoxins have been identified from C. marmoreus , Conus leopardus and Conus quercinus . Most of the above novel conotoxins belong to M‐1 and M‐2 and only one to M‐3. The disulfide analyses of two M ‐1 conotoxins, mr3e and tx3a, revealed that they possess a new disulfide bond arrangement (C1–C5, C2–C4, C3–C6) which is different from those of the M‐4 branch (C1–C4, C2–C5, C3–C6) and M‐2 branch (C1–C6, C2–C4, C3–C5). This newly characterized disulfide connectivity was confirmed by comparing the HPLC profiles of native mr3e and its two regioselectively folded isoforms. This is the first report of three different patterns of disulfide connectivity in conotoxins with the same cysteine framework.

Conotoxin

Linkage (software)

Disulfide Linkage

Characterization

10.1111/j.1742-4658.2006.05493.x

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Citations (50)

Molecular cloning, expression and characterization of protein disulfide isomerase from Conus marmoreus

FEBS Journal (2007)

Zhiqiang Wang Yu‐Hong Han Xiao‐Xia Shao Cheng‐Wu Chi Zhan‐Yun Guo

The oxidative folding of disulfide‐rich conotoxins is essential for their biological functions. In vivo , disulfide bond formation is mainly catalyzed by protein disulfide isomerase. To elucidate the physiologic roles of protein disulfide isomerase in the folding of conotoxins, we have cloned a novel full‐length protein disulfide isomerase from Conus marmoreus. Its ORF encodes a 500 amino acid protein that shares sequence homology with protein disulfide isomerases from other species, and 70% homology with human protein disulfide isomerase. Enzymatic analyses of recombinant C. marmoreus protein disulfide isomerase showed that it shared functional similarities with human protein disulfide isomerase. Using conotoxins tx3a and sTx3.1 as substrate, we analyzed the oxidase and isomerase activities of the C. marmoreus protein disulfide isomerase and found that it was much more efficient than glutathione in catalyzing oxidative folding and disulfide isomerization of conotoxins. We further demonstrated that macromolecular crowding had little effect on the protein disulfide isomerase‐catalyzed oxidative folding and disulfide isomerization of conotoxins. On the basis of these data, we propose that the C. marmoreus protein disulfide isomerase plays a key role during in vivo folding of conotoxins.

Oxidative folding

Foldase

Conotoxin

10.1111/j.1742-4658.2007.06003.x

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Citations (19)

HIF-1α regulates DcR3 to promote the development of endometriosis

European Journal of Obstetrics & Gynecology and Reproductive Biology (2024)

Jianhua Guan Xuhong Huang Ziyang Zhou Shaojing Li Fengmian Wang

The aim of this study was to investigate the expression and clinical significance of HIF-1α and DcR3 in endometriosis by analysing clinical case data. Tissue samples were collected for tissue chip analysis and staining, and human endometrial stromal cells were isolated and cultured for cell experiments. Additionally, experiments were conducted on collected peritoneal fluid to explore the association and role of HIF-1α and DcR3 in endometriosis.

Clinical Significance

Hypoxia

10.1016/j.ejogrb.2024.02.035

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Solution structure of an M‐1 conotoxin with a novel disulfide linkage

FEBS Journal (2007)

Weihong Du Yu‐Hong Han Feijuan Huang Juan Li Cheng‐Wu Chi

The M‐superfamily of conotoxins has a typical Cys framework (‐CC‐C‐C‐CC‐), and is one of the eight major superfamilies found in the venom of the cone snail. Depending on the number of residues located in the last Cys loop (between Cys4 and Cys5), the M‐superfamily family can be divided into four branches, namely M‐1, ‐2, ‐3 and ‐4. Recently, two M‐1 branch conotoxins (mr3e and tx3a) have been reported to possess a new disulfide bond arrangement between Cys1 and Cys5, Cys2 and Cys4, and Cys3 and Cys6, which is different from those seen in the M‐2 and M‐4 branches. Here we report the 3D structure of mr3e determined by 2D 1 H NMR in aqueous solution. Twenty converged structures of this peptide were obtained on the basis of 190 distance constraints obtained from NOE connectivities, as well as six ϕ dihedral angle, three hydrogen bond, and three disulfide bond constraints. The rmsd values about the averaged coordinates of the backbone atoms were 0.43 ± 0.19 Å. Although mr3e has the same Cys arrangement as M‐2 and M‐4 conotoxins, it adopts a distinctive backbone conformation with the overall molecule resembling a ‘flying bird’. Thus, different disulfide linkages may be employed by conotoxins with the same Cys framework to result in a more diversified backbone scaffold.

Dihedral angle

Conotoxin

Disulfide Linkage

10.1111/j.1742-4658.2007.05795.x

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Citations (29)

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

Journal of Biological Chemistry (2016)

Daniel R. Dries Yi Zhu Mieu Brooks Diego A. Forero Megumi Adachi

The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of γ-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate γ-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessive-compulsive disorder is a distinct subtype of schizophrenia. The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of γ-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate γ-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessive-compulsive disorder is a distinct subtype of schizophrenia.

Nicastrin

Neurodevelopmental disorder

10.1074/jbc.m116.715078

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Citations (18)

Glu-333 of Nicastrin Directly Participates in γ-Secretase Activity

Journal of Biological Chemistry (2009)

Daniel R. Dries Sanjiv Shah Yu‐Hong Han Cong Yu Sophie Yu

Nicastrin

Gamma secretase

Alpha secretase

Ectodomain

10.1074/jbc.m109.038737

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Citations (65)

P1‐304: The role of Nicastrin in gamma‐secretase activity

Alzheimer s & Dementia (2010)

Gang Yu Daniel R. Dries Sanjiv Shah Yu‐Hong Han Cong Yu

Previously, we had shown that Nicastrin (NCT) serves as a receptor for gamma-secretase substrates by binding the N-terminus of substrates that had recently undergone ectodomain shedding. We reported that Glu333 plays an important role in activity. Recently it was reported that NCT-E333A interferes with gamma-secretase maturation, rather than activity per se. This challenge prompted us to revisit our model with refined techniques. We developed a novel radioligand binding assay to determine the number of gamma-secretase active sites for proper normalization. We also used a pre-endoproteolyzed presenilin construct (PS1-N/CTF) that bypasses NCT's role in maturation of the gamma-secretase complex. NCT-E333A indeed shows a loss of intrinsic gamma-secretase activity in the context of PS1-N/CTF due to loss of binding to substrates. Furthermore, the NCT ectodomain appears to closely juxtapose the membrane during substrate binding and/or activity. Glu333 of NCT directly participates in gamma-secretase activity by binding the N-terminus of substrates. The close apposition of NCT and the membrane suggests that NCT may cap the active site during catalysis.

Ectodomain

Nicastrin

Gamma secretase

10.1016/j.jalz.2010.05.857

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