The macromolecular architecture of extracellular domain of αNRXN1: Domain organization, flexibility, and insights into trans-synaptic disposition

Davide Comoletti; Meghan T. Miller; Cy M. Jeffries; Jennifer Wilson; Borries Demeler; Palmer Taylor; Jill Trewhella; Terunaga Nakagawa

doi:10.1016/j.str.2010.06.005

The macromolecular architecture of extracellular domain of αNRXN1: Domain organization, flexibility, and insights into trans-synaptic disposition

Davide Comoletti
, Meghan T. Miller
, Cy M. Jeffries
, Jennifer Wilson
, Borries Demeler
, Palmer Taylor
, Jill Trewhella
, Terunaga Nakagawa

Chemistry and Biochemistry

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Neurexins are multidomain synaptic cell-adhesion proteins that associate with multiple partnering proteins. Genetic evidence indicates that neurexins may contribute to autism, schizophrenia, and nicotine dependence. Using analytical ultracentrifugation, single-particle electron microscopy, and solution X-ray scattering, we obtained a three-dimensional structural model of the entire extracellular domain of neurexin-1α. This protein adopts a dimensionally asymmetric conformation that is monomeric in solution, with a maximum dimension of ∼170 Å. The extracellular domain of α-neurexin maintains a characteristic "Y" shape, whereby LNS domains 1-4 form an extended base of the "Y" and LNS5-6 the shorter arms. Moreover, two major regions of flexibility are present: one between EGF1 and LNS2, corresponding to splice site 1, another between LNS5 and 6. We thus provide the first structural insights into the architecture of the extracellular region of neurexin-1α, show how the protein may fit in the synaptic cleft, and how partnering proteins could bind simultaneously.

Original language	English
Pages (from-to)	1044-1053
Number of pages	10
Journal	Structure
Volume	18
Issue number	8
DOIs	https://doi.org/10.1016/j.str.2010.06.005
State	Published - Aug 2010

Funding

This work was supported by USPHS (grant R37 GM-18360 to P.T.), NIEHS (grant P42ES10337 to P.T.), U.S. Department of Energy (grant DE-FG02-05ER64026 to J.T.), Autism Speaks (grant 2617 to D.C.), and the John Merck Fund and Hellman Foundation (support to T.N.). We acknowledge the use of the UCSD Cryo-Electron Microscopy Facility which was supported by NIH grants 1S10RR20016 and GM033050 to Timothy S. Baker and a gift from the Agouron Institute to UCSD. AUC supercomputer analyses were supported by NSF Teragrid allocation TG-MCB070038 (B.D.). UltraScan development is supported by NIH-RR022000 (B.D.). Calculations on Lonestar were supported by NSF TeraGrid allocation TG-MCB070038 (BD). We thank Dennis Winge (University of Utah, UT) for quantitative amino acid analysis, and Majid Ghassemian, Department of Chemistry and Biochemistry, for MALDI-TOF analysis. We thank A. G. Porter of the National University of Singapore for the kind gift of the 3C protease plasmid. We thank Michael Baker (Protein Data Bank) for helpful discussion on homology modeling, and Greg Fuchs for excellent technical help during the preparation of the cleavable αNRXN construct.

Funders	Funder number
1S10RR20016
DE-FG02-05ER64026
R37GM033050
P42ES10337
Autism Speaks Inc.	2617
R37 GM-18360

Keywords

Molneuro

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10.1016/j.str.2010.06.005

Cite this

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title = "The macromolecular architecture of extracellular domain of αNRXN1: Domain organization, flexibility, and insights into trans-synaptic disposition",

abstract = "Neurexins are multidomain synaptic cell-adhesion proteins that associate with multiple partnering proteins. Genetic evidence indicates that neurexins may contribute to autism, schizophrenia, and nicotine dependence. Using analytical ultracentrifugation, single-particle electron microscopy, and solution X-ray scattering, we obtained a three-dimensional structural model of the entire extracellular domain of neurexin-1α. This protein adopts a dimensionally asymmetric conformation that is monomeric in solution, with a maximum dimension of ∼170 {\AA}. The extracellular domain of α-neurexin maintains a characteristic {"}Y{"} shape, whereby LNS domains 1-4 form an extended base of the {"}Y{"} and LNS5-6 the shorter arms. Moreover, two major regions of flexibility are present: one between EGF1 and LNS2, corresponding to splice site 1, another between LNS5 and 6. We thus provide the first structural insights into the architecture of the extracellular region of neurexin-1α, show how the protein may fit in the synaptic cleft, and how partnering proteins could bind simultaneously.",

keywords = "Molneuro",

author = "Davide Comoletti and Miller, \{Meghan T.\} and Jeffries, \{Cy M.\} and Jennifer Wilson and Borries Demeler and Palmer Taylor and Jill Trewhella and Terunaga Nakagawa",

note = "Funding Information: This work was supported by USPHS (grant R37 GM-18360 to P.T.), NIEHS (grant P42ES10337 to P.T.), U.S. Department of Energy (grant DE-FG02-05ER64026 to J.T.), Autism Speaks (grant 2617 to D.C.), and the John Merck Fund and Hellman Foundation (support to T.N.). We acknowledge the use of the UCSD Cryo-Electron Microscopy Facility which was supported by NIH grants 1S10RR20016 and GM033050 to Timothy S. Baker and a gift from the Agouron Institute to UCSD. AUC supercomputer analyses were supported by NSF Teragrid allocation TG-MCB070038 (B.D.). UltraScan development is supported by NIH-RR022000 (B.D.). Calculations on Lonestar were supported by NSF TeraGrid allocation TG-MCB070038 (BD). We thank Dennis Winge (University of Utah, UT) for quantitative amino acid analysis, and Majid Ghassemian, Department of Chemistry and Biochemistry, for MALDI-TOF analysis. We thank A. G. Porter of the National University of Singapore for the kind gift of the 3C protease plasmid. We thank Michael Baker (Protein Data Bank) for helpful discussion on homology modeling, and Greg Fuchs for excellent technical help during the preparation of the cleavable αNRXN construct. ",

year = "2010",

month = aug,

doi = "10.1016/j.str.2010.06.005",

language = "English",

volume = "18",

pages = "1044--1053",

journal = "Structure",

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T1 - The macromolecular architecture of extracellular domain of αNRXN1

T2 - Domain organization, flexibility, and insights into trans-synaptic disposition

AU - Comoletti, Davide

AU - Miller, Meghan T.

AU - Jeffries, Cy M.

AU - Wilson, Jennifer

AU - Demeler, Borries

AU - Taylor, Palmer

AU - Trewhella, Jill

AU - Nakagawa, Terunaga

N1 - Funding Information: This work was supported by USPHS (grant R37 GM-18360 to P.T.), NIEHS (grant P42ES10337 to P.T.), U.S. Department of Energy (grant DE-FG02-05ER64026 to J.T.), Autism Speaks (grant 2617 to D.C.), and the John Merck Fund and Hellman Foundation (support to T.N.). We acknowledge the use of the UCSD Cryo-Electron Microscopy Facility which was supported by NIH grants 1S10RR20016 and GM033050 to Timothy S. Baker and a gift from the Agouron Institute to UCSD. AUC supercomputer analyses were supported by NSF Teragrid allocation TG-MCB070038 (B.D.). UltraScan development is supported by NIH-RR022000 (B.D.). Calculations on Lonestar were supported by NSF TeraGrid allocation TG-MCB070038 (BD). We thank Dennis Winge (University of Utah, UT) for quantitative amino acid analysis, and Majid Ghassemian, Department of Chemistry and Biochemistry, for MALDI-TOF analysis. We thank A. G. Porter of the National University of Singapore for the kind gift of the 3C protease plasmid. We thank Michael Baker (Protein Data Bank) for helpful discussion on homology modeling, and Greg Fuchs for excellent technical help during the preparation of the cleavable αNRXN construct.

PY - 2010/8

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N2 - Neurexins are multidomain synaptic cell-adhesion proteins that associate with multiple partnering proteins. Genetic evidence indicates that neurexins may contribute to autism, schizophrenia, and nicotine dependence. Using analytical ultracentrifugation, single-particle electron microscopy, and solution X-ray scattering, we obtained a three-dimensional structural model of the entire extracellular domain of neurexin-1α. This protein adopts a dimensionally asymmetric conformation that is monomeric in solution, with a maximum dimension of ∼170 Å. The extracellular domain of α-neurexin maintains a characteristic "Y" shape, whereby LNS domains 1-4 form an extended base of the "Y" and LNS5-6 the shorter arms. Moreover, two major regions of flexibility are present: one between EGF1 and LNS2, corresponding to splice site 1, another between LNS5 and 6. We thus provide the first structural insights into the architecture of the extracellular region of neurexin-1α, show how the protein may fit in the synaptic cleft, and how partnering proteins could bind simultaneously.

AB - Neurexins are multidomain synaptic cell-adhesion proteins that associate with multiple partnering proteins. Genetic evidence indicates that neurexins may contribute to autism, schizophrenia, and nicotine dependence. Using analytical ultracentrifugation, single-particle electron microscopy, and solution X-ray scattering, we obtained a three-dimensional structural model of the entire extracellular domain of neurexin-1α. This protein adopts a dimensionally asymmetric conformation that is monomeric in solution, with a maximum dimension of ∼170 Å. The extracellular domain of α-neurexin maintains a characteristic "Y" shape, whereby LNS domains 1-4 form an extended base of the "Y" and LNS5-6 the shorter arms. Moreover, two major regions of flexibility are present: one between EGF1 and LNS2, corresponding to splice site 1, another between LNS5 and 6. We thus provide the first structural insights into the architecture of the extracellular region of neurexin-1α, show how the protein may fit in the synaptic cleft, and how partnering proteins could bind simultaneously.

KW - Molneuro

UR - https://www.scopus.com/pages/publications/77955504111

U2 - 10.1016/j.str.2010.06.005

DO - 10.1016/j.str.2010.06.005

M3 - Article

C2 - 20696403

AN - SCOPUS:77955504111

SN - 0969-2126

VL - 18

SP - 1044

EP - 1053

JO - Structure

JF - Structure

IS - 8

ER -

The macromolecular architecture of extracellular domain of αNRXN1: Domain organization, flexibility, and insights into trans-synaptic disposition

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Keywords

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