Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion

Dietmar Schreiner; Joshua A Weiner

doi:10.1073/pnas.1004526107

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Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion

Journal article

Open access

Peer reviewed

Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion

Dietmar Schreiner and Joshua A Weiner

Proceedings of the National Academy of Sciences - PNAS, Vol.107(33), pp.14893-14898

08/17/2010

DOI: 10.1073/pnas.1004526107

PMCID: PMC2930437

PMID: 20679223

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Abstract

The specificity of interactions between neurons is believed to be mediated by diverse cell adhesion molecules, including members of the cadherin superfamily. Whereas mechanisms of classical cadherin adhesion have been studied extensively, much less is known about the related protocadherins (Pcdhs), which together make up the majority of the superfamily. Here we use quantitative cell aggregation assays and biochemical analyses to characterize cis and trans interactions among the 22-member gamma-Pcdh family, which have been shown to be critical for the control of synaptogenesis and neuronal survival. We show that gamma-Pcdh isoforms engage in trans interactions that are strictly homophilic. In contrast to classical cadherins, gamma-Pcdh interactions are only partially Ca(2+)-dependent, and their specificity is mediated through the second and third extracellular cadherin (EC) domains (EC2 and EC3), rather than through EC1. The gamma-Pcdhs also interact both covalently and noncovalently in the cis-orientation to form multimers both in vitro and in vivo. In contrast to gamma-Pcdh trans interactions, cis interactions are highly promiscuous, with no isoform specificity. We present data supporting a model in which gamma-Pcdh cis-tetramers represent the unit of their adhesive trans interactions. Unrestricted tetramerization in cis, coupled with strictly homophilic interactions in trans, predicts that the 22 gamma-Pcdhs could form 234,256 distinct adhesive interfaces. Given the demonstrated role of the gamma-Pcdhs in synaptogenesis, our data have important implications for the molecular control of neuronal specificity.

Cadherins - metabolism

Humans

Protein Multimerization

Cercopithecus aethiops

Neurons - cytology

Green Fluorescent Proteins - genetics

Protein Isoforms - metabolism

Transfection

Protein Isoforms - chemistry

Cadherins - chemistry

Neurons - metabolism

Cadherins - genetics

Cell Line

Green Fluorescent Proteins - metabolism

Intercellular Junctions - metabolism

Cell Communication

Binding Sites - genetics

Cell Adhesion

Blotting, Western

Animals

Fluorescent Antibody Technique

K562 Cells

Protein Binding

Mice

Mutation

COS Cells

Protein Isoforms - genetics

Details

Title: Subtitle: Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion
Creators: Dietmar Schreiner - Department of Biology, University of Iowa, Iowa City, IA 52242, USA
Joshua A Weiner
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.107(33), pp.14893-14898
DOI: 10.1073/pnas.1004526107
PMID: 20679223
PMCID: PMC2930437
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: NS055272 / NINDS NIH HHS R01 NS055272 / NINDS NIH HHS
Language: English
Date published: 08/17/2010
Academic Unit: Liberal Arts and Science Admin; Psychiatry; Iowa Neuroscience Institute; Biology
Record Identifier: 9983997988002771

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