Structure and Sequence Analyses of Clustered Protocadherins Reveal Antiparallel Interactions that Mediate Homophilic Specificity.
Clustered protocadherin (Pcdh) proteins mediate dendritic self-avoidance in neurons via specific homophilic interactions in their extracellular cadherin (EC) domains. We determined crystal structures of EC1-EC3, containing the homophilic specificity-determining region, of two mouse clustered Pcdh isoforms (PcdhγA1 and PcdhγC3) to investigate the nature of the homophilic interaction. Within the crystal lattices, we observe antiparallel interfaces consistent with a role in trans cell-cell contact. Antiparallel dimerization is supported by evolutionary correlations. Two interfaces, located primarily on EC2-EC3, involve distinctive clustered Pcdh structure and sequence motifs, lack predicted glycosylation sites, and contain residues highly conserved in orthologs but not paralogs, pointing toward their biological significance as homophilic interaction interfaces. These two interfaces are similar yet distinct, reflecting a possible difference in interaction architecture between clustered Pcdh subfamilies. These structures initiate a molecular understanding of clustered Pcdh assemblies that are required to produce functional neuronal networks.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
John M
JM
Nicoludis
Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
Sze-Yi
SY
Lau
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Applied Bioinformatics, Department of Computer Science, University of Tübingen, Tübingen 72076, Germany.
Charlotta P I
CP
Schärfe
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Debora S
DS
Marks
Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA. Electronic address: wilhelm.weihofen@novartis.com.
Wilhelm A
WA
Weihofen
Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA. Electronic address: gaudet@mcb.harvard.edu.
Rachelle
R
Gaudet
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism; D017124:Conserved Sequence; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D000091363:Protocadherins
D015820:Cadherins; C504473:Pcdh1 protein, mouse; D020033:Protein Isoforms; D000091363:Protocadherins