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Title: Protocadherin cis-dimer architecture and recognition unit diversity

Abstract

Clustered protocadherins (Pcdhs) mediate numerous neural patterning functions, including neuronal self-recognition and non–self-discrimination to direct self-avoidance among vertebrate neurons. Individual neurons stochastically express a subset of Pcdh isoforms, which assemble to form a stochastic repertoire ofcis-dimers. We describe herein the structure of a PcdhγB7cis-homodimer, which includes the membrane-proximal extracellular cadherin domains EC5 and EC6. The structure is asymmetric with one molecule contributing interface surface from both EC5 and EC6, and the other only from EC6. Structural and sequence analyses suggest that all Pcdh isoforms will dimerize through this interface. Site-directed mutants at this interface interfere with both Pcdhcis-dimerization and cell surface transport. The structure explains the known restrictions ofcis-interactions of some Pcdh isoforms, including α-Pcdhs, which cannot form homodimers. The asymmetry of the interface approximately doubles the size of the recognition repertoire, and restrictions oncis-interactions among Pcdh isoforms define the limits of the Pcdh recognition unit repertoire.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Columbia Univ., New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); National Science Foundation (NSF)
OSTI Identifier:
1430316
Grant/Contract Number:  
[P41GM103403; MCB-1412472; R01GM107571; R01MH114817; S10OD012351; S10OD021764]
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
[ Journal Volume: 114; Journal Issue: 46]; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; clustered protocadherin; crystal structure; protein–protein interaction; neuronal self-avoidance; self-recognition

Citation Formats

Goodman, Kerry M., Rubinstein, Rotem, Dan, Hanbin, Bahna, Fabiana, Mannepalli, Seetha, Ahlsén, Göran, Aye Thu, Chan, Sampogna, Rosemary V., Maniatis, Tom, Honig, Barry, and Shapiro, Lawrence. Protocadherin cis-dimer architecture and recognition unit diversity. United States: N. p., 2017. Web. doi:10.1073/pnas.1713449114.
Goodman, Kerry M., Rubinstein, Rotem, Dan, Hanbin, Bahna, Fabiana, Mannepalli, Seetha, Ahlsén, Göran, Aye Thu, Chan, Sampogna, Rosemary V., Maniatis, Tom, Honig, Barry, & Shapiro, Lawrence. Protocadherin cis-dimer architecture and recognition unit diversity. United States. doi:10.1073/pnas.1713449114.
Goodman, Kerry M., Rubinstein, Rotem, Dan, Hanbin, Bahna, Fabiana, Mannepalli, Seetha, Ahlsén, Göran, Aye Thu, Chan, Sampogna, Rosemary V., Maniatis, Tom, Honig, Barry, and Shapiro, Lawrence. Mon . "Protocadherin cis-dimer architecture and recognition unit diversity". United States. doi:10.1073/pnas.1713449114. https://www.osti.gov/servlets/purl/1430316.
@article{osti_1430316,
title = {Protocadherin cis-dimer architecture and recognition unit diversity},
author = {Goodman, Kerry M. and Rubinstein, Rotem and Dan, Hanbin and Bahna, Fabiana and Mannepalli, Seetha and Ahlsén, Göran and Aye Thu, Chan and Sampogna, Rosemary V. and Maniatis, Tom and Honig, Barry and Shapiro, Lawrence},
abstractNote = {Clustered protocadherins (Pcdhs) mediate numerous neural patterning functions, including neuronal self-recognition and non–self-discrimination to direct self-avoidance among vertebrate neurons. Individual neurons stochastically express a subset of Pcdh isoforms, which assemble to form a stochastic repertoire ofcis-dimers. We describe herein the structure of a PcdhγB7cis-homodimer, which includes the membrane-proximal extracellular cadherin domains EC5 and EC6. The structure is asymmetric with one molecule contributing interface surface from both EC5 and EC6, and the other only from EC6. Structural and sequence analyses suggest that all Pcdh isoforms will dimerize through this interface. Site-directed mutants at this interface interfere with both Pcdhcis-dimerization and cell surface transport. The structure explains the known restrictions ofcis-interactions of some Pcdh isoforms, including α-Pcdhs, which cannot form homodimers. The asymmetry of the interface approximately doubles the size of the recognition repertoire, and restrictions oncis-interactions among Pcdh isoforms define the limits of the Pcdh recognition unit repertoire.},
doi = {10.1073/pnas.1713449114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = [46],
volume = [114],
place = {United States},
year = {2017},
month = {10}
}

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Works referenced in this record:

Structure and Sequence Analyses of Clustered Protocadherins Reveal Antiparallel Interactions that Mediate Homophilic Specificity
journal, November 2015


Protocadherin-  Family Is Required for Serotonergic Projections to Appropriately Innervate Target Brain Areas
journal, July 2009


Developmental Epigenetic Modification Regulates Stochastic Expression of Clustered Protocadherin Genes, Generating Single Neuron Diversity
journal, April 2014


Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4
journal, July 2016


Stereological Estimation of Olfactory Receptor Neurons in Rats
journal, December 2014


Protocadherins mediate dendritic self-avoidance in the mammalian nervous system
journal, July 2012

  • Lefebvre, Julie L.; Kostadinov, Dimitar; Chen, Weisheng V.
  • Nature, Vol. 488, Issue 7412
  • DOI: 10.1038/nature11305

Clustered protocadherins
journal, July 2013


Impaired clustered protocadherin-α leads to aggregated retinogeniculate terminals and impaired visual acuity in mice
journal, February 2015

  • Meguro, Reiko; Hishida, Ryuichi; Tsukano, Hiroaki
  • Journal of Neurochemistry, Vol. 133, Issue 1
  • DOI: 10.1111/jnc.13053

Molecular codes for neuronal individuality and cell assembly in the brain
journal, January 2012


Stochastic yet biased expression of multiple Dscam splice variants by individual cells
journal, February 2004

  • Neves, Guilherme; Zucker, Jacob; Daly, Mark
  • Nature Genetics, Vol. 36, Issue 3
  • DOI: 10.1038/ng1299

Allelic Gene Regulation of Pcdh- α and Pcdh- γ Clusters Involving Both Monoallelic and Biallelic Expression in Single Purkinje Cells
journal, August 2006

  • Kaneko, Ryosuke; Kato, Hiroyuki; Kawamura, Yoshimi
  • Journal of Biological Chemistry, Vol. 281, Issue 41
  • DOI: 10.1074/jbc.M605677200

Constitutively expressed Protocadherin-α regulates the coalescence and elimination of homotypic olfactory axons through its cytoplasmic region
journal, January 2012

  • Hasegawa, Sonoko; Hirabayashi, Takahiro; Kondo, Takahiko
  • Frontiers in Molecular Neuroscience, Vol. 5
  • DOI: 10.3389/fnmol.2012.00097

Single-Cell Identity Generated by Combinatorial Homophilic Interactions between α, β, and γ Protocadherins
journal, August 2014


γ-Protocadherin structural diversity and functional implications
journal, October 2016

  • Goodman, Kerry Marie; Rubinstein, Rotem; Thu, Chan Aye
  • eLife, Vol. 5
  • DOI: 10.7554/eLife.20930

Single-neuron diversity generated by Protocadherin-β cluster in mouse central and peripheral nervous systems
journal, January 2012

  • Hirano, Keizo; Kaneko, Ryosuke; Izawa, Takeshi
  • Frontiers in Molecular Neuroscience, Vol. 5
  • DOI: 10.3389/fnmol.2012.00090

SignalP 4.0: discriminating signal peptides from transmembrane regions
journal, September 2011

  • Petersen, Thomas Nordahl; Brunak, Søren; von Heijne, Gunnar
  • Nature Methods, Vol. 8, Issue 10
  • DOI: 10.1038/nmeth.1701

Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase
journal, June 2012

  • Suo, Lun; Lu, Huinan; Ying, Guoxin
  • Journal of Molecular Cell Biology, Vol. 4, Issue 6
  • DOI: 10.1093/jmcb/mjs034

 -Protocadherins regulate neuronal survival but are dispensable for circuit formation in retina
journal, December 2008

  • Lefebvre, J. L.; Zhang, Y.; Meister, M.
  • Development, Vol. 135, Issue 24
  • DOI: 10.1242/dev.027912

Promoter Choice Determines Splice Site Selection in Protocadherin α and γ Pre-mRNA Splicing
journal, July 2002


How good are my data and what is the resolution?
journal, June 2013

  • Evans, Philip R.; Murshudov, Garib N.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7
  • DOI: 10.1107/S0907444913000061

Alternative Splicing of Drosophila Dscam Generates Axon Guidance Receptors that Exhibit Isoform-Specific Homophilic Binding
journal, September 2004


XDS
journal, January 2010

  • Kabsch, Wolfgang
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
  • DOI: 10.1107/S0907444909047337

Inference of Macromolecular Assemblies from Crystalline State
journal, September 2007


UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004

  • Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.
  • Journal of Computational Chemistry, Vol. 25, Issue 13
  • DOI: 10.1002/jcc.20084

WebLogo: A Sequence Logo Generator
journal, May 2004

  • Crooks, Gavin E.; Hon, Gary; Chandonia, John-Marc
  • Genome Research, Vol. 14, Issue 6, p. 1188-1190
  • DOI: 10.1101/gr.849004

The protocadherin-α family is involved in axonal coalescence of olfactory sensory neurons into glomeruli of the olfactory bulb in mouse
journal, May 2008

  • Hasegawa, Sonoko; Hamada, Shun; Kumode, You
  • Molecular and Cellular Neuroscience, Vol. 38, Issue 1
  • DOI: 10.1016/j.mcn.2008.01.016

Distinct and Cooperative Functions for the Protocadherin-α, -β and -γ Clusters in Neuronal Survival and Axon Targeting
journal, December 2016

  • Hasegawa, Sonoko; Kumagai, Makiko; Hagihara, Mitsue
  • Frontiers in Molecular Neuroscience, Vol. 9
  • DOI: 10.3389/fnmol.2016.00155

Analysis of Dscam Diversity in Regulating Axon Guidance in Drosophila Mushroom Bodies
journal, September 2004


Down-regulation of protocadherin-α A isoforms in mice changes contextual fear conditioning and spatial working memory
journal, October 2008


Interaction with Protocadherin-γ Regulates the Cell Surface Expression of Protocadherin-α
journal, September 2004

  • Murata, Yoji; Hamada, Shun; Morishita, Hirofumi
  • Journal of Biological Chemistry, Vol. 279, Issue 47
  • DOI: 10.1074/jbc.M408771200

Deciphering key features in protein structures with the new ENDscript server
journal, April 2014

  • Robert, Xavier; Gouet, Patrice
  • Nucleic Acids Research, Vol. 42, Issue W1
  • DOI: 10.1093/nar/gku316

Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Homophilic Protocadherin Cell-Cell Interactions Promote Dendrite Complexity
journal, May 2016


Gamma protocadherins are required for synaptic development in the spinal cord
journal, December 2004

  • Weiner, J. A.; Wang, X.; Tapia, J. C.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 1
  • DOI: 10.1073/pnas.0407931101

Multicluster Pcdh diversity is required for mouse olfactory neural circuit assembly
journal, April 2017

  • Mountoufaris, George; Chen, Weisheng V.; Hirabayashi, Yusuke
  • Science, Vol. 356, Issue 6336
  • DOI: 10.1126/science.aai8801

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

Combinatorial homophilic interaction between  -protocadherin multimers greatly expands the molecular diversity of cell adhesion
journal, August 2010

  • Schreiner, D.; Weiner, J. A.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 33
  • DOI: 10.1073/pnas.1004526107

Molecular Logic of Neuronal Self-Recognition through Protocadherin Domain Interactions
journal, October 2015


Pcdhαc2 is required for axonal tiling and assembly of serotonergic circuitries in mice
journal, April 2017

  • Chen, Weisheng V.; Nwakeze, Chiamaka L.; Denny, Christine A.
  • Science, Vol. 356, Issue 6336
  • DOI: 10.1126/science.aal3231

Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega
journal, January 2011

  • Sievers, Fabian; Wilm, Andreas; Dineen, David
  • Molecular Systems Biology, Vol. 7, Issue 1
  • DOI: 10.1038/msb.2011.75

Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins
journal, May 2016


Visual Map Shifts based on Whisker-Guided Cues in the Young Mouse Visual Cortex
journal, December 2013


Comparative DNA Sequence Analysis of Mouse and Human Protocadherin Gene Clusters
journal, March 2001


The Molecular Basis of Self-Avoidance
journal, July 2013


Drosophila Dscam Is an Axon Guidance Receptor Exhibiting Extraordinary Molecular Diversity
journal, June 2000


Probabilistic Splicing of Dscam1 Establishes Identity at the Level of Single Neurons
journal, November 2013


γ-Protocadherins Control Cortical Dendrite Arborization by Regulating the Activity of a FAK/PKC/MARCKS Signaling Pathway
journal, April 2012


A Vast Repertoire of Dscam Binding Specificities Arises from Modular Interactions of Variable Ig Domains
journal, September 2007


Age-induced disruption of selective olfactory bulb synaptic circuits
journal, August 2010

  • Richard, M. B.; Taylor, S. R.; Greer, C. A.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 35
  • DOI: 10.1073/pnas.1007931107

Functional Significance of Isoform Diversification in the Protocadherin Gamma Gene Cluster
journal, August 2012


Monoallelic yet combinatorial expression of variable exons of the protocadherin-α gene cluster in single neurons
journal, January 2005

  • Esumi, Shigeyuki; Kakazu, Naoki; Taguchi, Yusuke
  • Nature Genetics, Vol. 37, Issue 2
  • DOI: 10.1038/ng1500

Direct and Indirect Regulation of Spinal Cord Ia Afferent Terminal Formation by the γ-Protocadherins
journal, January 2011


Regulation of neural circuit formation by protocadherins
journal, June 2017

  • Peek, Stacey L.; Mah, Kar Men; Weiner, Joshua A.
  • Cellular and Molecular Life Sciences, Vol. 74, Issue 22
  • DOI: 10.1007/s00018-017-2572-3

Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

Recurrent turnover of senescent cells during regeneration of a complex structure
journal, May 2015

  • Yun, Maximina H.; Davaapil, Hongorzul; Brockes, Jeremy P.
  • eLife, Vol. 4
  • DOI: 10.7554/eLife.05505