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  1. Article ; Online: Structure of Reelin repeat 8 and the adjacent C-terminal region.

    Turk, Liam S / Currie, Michael J / Dobson, Renwick C J / Comoletti, Davide

    Biophysical journal

    2022  Volume 121, Issue 13, Page(s) 2526–2537

    Abstract: Neuronal development and function are dependent in part on the several roles of the secreted glycoprotein Reelin. Endogenous proteases process this 400 kDa, modular protein, yielding N-terminal, central, and C-terminal fragments that each have distinct ... ...

    Abstract Neuronal development and function are dependent in part on the several roles of the secreted glycoprotein Reelin. Endogenous proteases process this 400 kDa, modular protein, yielding N-terminal, central, and C-terminal fragments that each have distinct roles in Reelin's function and regulation. The C-terminal fragment comprises Reelin repeat (RR) domains seven and eight, as well as a basic stretch of 32 amino acid residues termed the C-terminal region (CTR), influences Reelin signaling intensity, and has been reported to bind to Neuropilin-1, which serves as a co-receptor in the canonical Reelin signaling pathway. Here, we present a crystal structure of RR8 at 3.0 Å resolution. Analytical ultracentrifugation and small-angle x-ray scattering confirmed that RR8 is monomeric and enabled us to identify the CTR as a flexible, yet compact subdomain. We conducted structurally informed protein engineering to design a chimeric RR8 construct guided by the structural similarities with RR6. Experimental results support a mode of Reelin-receptor interaction reliant on the multiple interfaces coordinating the binding event. Structurally, RR8 resembles other individual RRs, but its structure does show discrete differences that may account for Reelin receptor specificity toward RR6.
    MeSH term(s) Cell Adhesion Molecules, Neuronal/chemistry ; Extracellular Matrix Proteins/genetics ; Nerve Tissue Proteins/chemistry ; Neurons/metabolism ; Reelin Protein ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism
    Chemical Substances Cell Adhesion Molecules, Neuronal ; Extracellular Matrix Proteins ; Nerve Tissue Proteins ; Reelin Protein ; Serine Endopeptidases (EC 3.4.21.-)
    Language English
    Publishing date 2022-06-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2022.06.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 235: Show issues Location:
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    Zs.MO 2: Show issues

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  2. Article ; Online: Purification of a heterodimeric Reelin construct to investigate binding stoichiometry.

    Turk, Liam S / Mitchell, Daniel / Comoletti, Davide

    European biophysics journal : EBJ

    2020  Volume 49, Issue 8, Page(s) 773–779

    Abstract: Reelin is a secreted glycoprotein that is integral in neocortex development and synaptic function. Reelin exists as a homodimer with two chains linked by a disulfide bond at cysteine 2101, a feature that is vital to the protein's function. This is ... ...

    Abstract Reelin is a secreted glycoprotein that is integral in neocortex development and synaptic function. Reelin exists as a homodimer with two chains linked by a disulfide bond at cysteine 2101, a feature that is vital to the protein's function. This is highlighted by the fact that only dimeric Reelin can elicit efficient, canonical signaling, even though a mutated (C2101A) monomeric construct of Reelin retains the capacity to bind to its receptors. Receptor clustering has been shown to be important in the signaling pathway, however direct evidence regarding the stoichiometry of Reelin-receptor binding interaction is lacking. Here we describe the construction and purification of a heterodimeric Reelin construct to investigate the stoichiometry of Reelin-receptor binding and how it affects Reelin pathway signaling. We have devised different strategies and have finalized a protocol to produce a heterodimer of Reelin's central fragment using differential tagging and tandem affinity chromatography, such that chain A is wild type in amino acid sequence whereas chain B includes a receptor binding site mutation (K2467A). We also validate that the heterodimer is capable of binding to the extracellular domain of one of Reelin's known receptors, calculating the K
    MeSH term(s) Cell Adhesion Molecules, Neuronal/chemistry ; Cell Adhesion Molecules, Neuronal/isolation & purification ; Cell Adhesion Molecules, Neuronal/metabolism ; Extracellular Matrix Proteins/chemistry ; Extracellular Matrix Proteins/isolation & purification ; Extracellular Matrix Proteins/metabolism ; HEK293 Cells ; Humans ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/isolation & purification ; Nerve Tissue Proteins/metabolism ; Neurons/cytology ; Neurons/metabolism ; Protein Binding ; Protein Multimerization ; Protein Structure, Quaternary ; Reelin Protein ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/isolation & purification ; Serine Endopeptidases/metabolism ; Signal Transduction
    Chemical Substances Cell Adhesion Molecules, Neuronal ; Extracellular Matrix Proteins ; Nerve Tissue Proteins ; Reelin Protein ; RELN protein, human (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
    Language English
    Publishing date 2020-10-14
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 283671-3
    ISSN 1432-1017 ; 0175-7571
    ISSN (online) 1432-1017
    ISSN 0175-7571
    DOI 10.1007/s00249-020-01465-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1121: Show issues Location:
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  3. Article ; Online: The structure-function relationship of a signaling-competent, dimeric Reelin fragment.

    Turk, Liam S / Kuang, Xuyuan / Dal Pozzo, Valentina / Patel, Khush / Chen, Muyuan / Huynh, Kevin / Currie, Michael J / Mitchell, Daniel / Dobson, Renwick C J / D'Arcangelo, Gabriella / Dai, Wei / Comoletti, Davide

    Structure (London, England : 1993)

    2021  Volume 29, Issue 10, Page(s) 1156–1170.e6

    Abstract: Reelin operates through canonical and non-canonical pathways that mediate several aspects of brain development and function. Reelin's dimeric central fragment (CF), generated through proteolytic cleavage, is required for the lipoprotein-receptor- ... ...

    Abstract Reelin operates through canonical and non-canonical pathways that mediate several aspects of brain development and function. Reelin's dimeric central fragment (CF), generated through proteolytic cleavage, is required for the lipoprotein-receptor-dependent canonical pathway activation. Here, we analyze the signaling properties of a variety of Reelin fragments and measure the differential binding affinities of monomeric and dimeric CF fragments to lipoprotein receptors to investigate the mode of canonical signal activation. We also present the cryoelectron tomography-solved dimeric structure of Reelin CF and support it using several other biophysical techniques. Our findings suggest that Reelin CF forms a covalent parallel dimer with some degree of flexibility between the two protein chains. As a result of this conformation, Reelin binds to lipoprotein receptors in a manner inaccessible to its monomeric form and is capable of stimulating canonical pathway signaling.
    MeSH term(s) Cryoelectron Microscopy ; HEK293 Cells ; Humans ; Protein Domains ; Protein Multimerization ; Receptors, LDL/metabolism ; Reelin Protein/chemistry ; Reelin Protein/metabolism ; Signal Transduction
    Chemical Substances Receptors, LDL ; Reelin Protein ; VLDL receptor ; RELN protein, human (EC 3.4.21.-)
    Language English
    Publishing date 2021-06-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1213087-4
    ISSN 1878-4186 ; 0969-2126
    ISSN (online) 1878-4186
    ISSN 0969-2126
    DOI 10.1016/j.str.2021.05.012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4141: Show issues Location:
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  4. Article ; Online: A Proteomic Screen of Neuronal Cell-Surface Molecules Reveals IgLONs as Structurally Conserved Interaction Modules at the Synapse.

    Ranaivoson, Fanomezana M / Turk, Liam S / Ozgul, Sinem / Kakehi, Sumie / von Daake, Sventja / Lopez, Nicole / Trobiani, Laura / De Jaco, Antonella / Denissova, Natalia / Demeler, Borries / Özkan, Engin / Montelione, Gaetano T / Comoletti, Davide

    Structure (London, England : 1993)

    2019  Volume 27, Issue 6, Page(s) 893–906.e9

    Abstract: In the developing brain, cell-surface proteins play crucial roles, but their protein-protein interaction network remains largely unknown. A proteomic screen identified 200 interactions, 89 of which were not previously published. Among these interactions, ...

    Abstract In the developing brain, cell-surface proteins play crucial roles, but their protein-protein interaction network remains largely unknown. A proteomic screen identified 200 interactions, 89 of which were not previously published. Among these interactions, we find that the IgLONs, a family of five cell-surface neuronal proteins implicated in various human disorders, interact as homo- and heterodimers. We reveal their interaction patterns and report the dimeric crystal structures of Neurotrimin (NTRI), IgLON5, and the neuronal growth regulator 1 (NEGR1)/IgLON5 complex. We show that IgLONs maintain an extended conformation and that their dimerization occurs through the first Ig domain of each monomer and is Ca
    MeSH term(s) Amino Acid Sequence ; Animals ; Brain/cytology ; Brain/metabolism ; Cell Adhesion Molecules, Neuronal/chemistry ; Cell Adhesion Molecules, Neuronal/genetics ; Cell Adhesion Molecules, Neuronal/metabolism ; GPI-Linked Proteins/chemistry ; GPI-Linked Proteins/genetics ; GPI-Linked Proteins/metabolism ; Humans ; Ligands ; Models, Molecular ; Neural Cell Adhesion Molecules/chemistry ; Neural Cell Adhesion Molecules/genetics ; Neural Cell Adhesion Molecules/metabolism ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Proteomics/methods ; Sequence Homology, Amino Acid ; Synapses/metabolism
    Chemical Substances Cell Adhesion Molecules, Neuronal ; GPI-Linked Proteins ; IgLON5 protein, human ; Ligands ; NEGR1 protein, human ; Neural Cell Adhesion Molecules ; neurotrimin
    Language English
    Publishing date 2019-04-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1213087-4
    ISSN 1878-4186 ; 0969-2126
    ISSN (online) 1878-4186
    ISSN 0969-2126
    DOI 10.1016/j.str.2019.03.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4141: Show issues Location:
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  5. Article ; Online: Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca

    Martín-de-Saavedra, M Dolores / Dos Santos, Marc / Culotta, Lorenza / Varea, Olga / Spielman, Benjamin P / Parnell, Euan / Forrest, Marc P / Gao, Ruoqi / Yoon, Sehyoun / McCoig, Emmarose / Jalloul, Hiba A / Myczek, Kristoffer / Khalatyan, Natalia / Hall, Elizabeth A / Turk, Liam S / Sanz-Clemente, Antonio / Comoletti, Davide / Lichtenthaler, Stefan F / Burgdorf, Jeffrey S /
    Barbolina, Maria V / Savas, Jeffrey N / Penzes, Peter

    Neuron

    2021  Volume 110, Issue 4, Page(s) 627–643.e9

    Abstract: Although many neuronal membrane proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding (ES). Here, we show that the neuronal sheddome is detectable in human cerebrospinal fluid (hCSF) and ... ...

    Abstract Although many neuronal membrane proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding (ES). Here, we show that the neuronal sheddome is detectable in human cerebrospinal fluid (hCSF) and is enriched in neurodevelopmental disorder (NDD) risk factors. Among shed synaptic proteins is the ectodomain of CNTNAP2 (CNTNAP2-ecto), a prominent NDD risk factor. CNTNAP2 undergoes activity-dependent ES via MMP9 (matrix metalloprotease 9), and CNTNAP2-ecto levels are reduced in the hCSF of individuals with autism spectrum disorder. Using mass spectrometry, we identified the plasma membrane Ca
    MeSH term(s) Autism Spectrum Disorder/cerebrospinal fluid ; Autism Spectrum Disorder/genetics ; Autism Spectrum Disorder/metabolism ; Cell Membrane/metabolism ; Homeostasis ; Humans ; Membrane Proteins/metabolism ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism ; Plasma Membrane Calcium-Transporting ATPases/cerebrospinal fluid ; Plasma Membrane Calcium-Transporting ATPases/genetics ; Plasma Membrane Calcium-Transporting ATPases/metabolism ; Signal Transduction
    Chemical Substances CNTNAP2 protein, human ; Membrane Proteins ; Nerve Tissue Proteins ; Plasma Membrane Calcium-Transporting ATPases (EC 3.6.3.8) ; ATP2B2 protein, human (EC 7.2.2.10)
    Language English
    Publishing date 2021-12-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2021.11.025
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MG 92: Show issues

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