CDB25:0004070 PCDHGB2 — PCDHGB2
Experimentally validated in Mouse; Orthology-inferred in Human, Zebrafish, Pig, Cow
Title
Journal:; Year Published:
Abstract
Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion.
Proceedings of the National Academy of Sciences of the United States of America, 2010; PubMed, Mus Musculus Pcdhgb2 — Mus Musculus Pcdhgb2
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.
Single-cell identity generated by combinatorial homophilic interactions between α, β, and γ protocadherins.
Cell, 2014; PubMed, Mus Musculus Pcdhgb2 — Mus Musculus Pcdhgb2
ABSTRACT: Individual mammalian neurons stochastically express distinct repertoires of α, β, and γ protocadherin (Pcdh) proteins, which function in neural circuit assembly. We report that all three subfamilies of clustered Pcdhs can engage in specific homophilic interactions, that cell surface delivery of Pcdhα isoforms requires cis interactions with other Pcdhs, and that the extracellular cadherin domain EC6 plays a critical role in this process. Examination of homophilic interactions between specific combinations of multiple Pcdh isoforms revealed that Pcdh combinatorial recognition specificities depend on the identity of all of the expressed isoforms. A single mismatched Pcdh isoform can interfere with these combinatorial homophilic interactions. A theoretical analysis reveals that assembly of Pcdh isoforms into multimeric recognition units and the observed tolerance for mismatched isoforms can generate cell surface diversity sufficient for single-cell identity. However, the competing demands of nonself discrimination and self-recognition place limitations on the mechanisms by which homophilic recognition units can function.
How clustered protocadherin binding specificity is tuned for neuronal self-/nonself-recognition.
eLife, 2022; PubMed, Mus Musculus Pcdhgb2 — Mus Musculus Pcdhgb2
ABSTRACT: The stochastic expression of fewer than 60 clustered protocadherin (cPcdh) isoforms provides diverse identities to individual vertebrate neurons and a molecular basis for self-/nonself-discrimination. cPcdhs form chains mediated by alternating cis and trans interactions between apposed membranes, which has been suggested to signal self-recognition. Such a mechanism requires that cPcdh cis dimers form promiscuously to generate diverse recognition units, and that trans interactions have precise specificity so that isoform mismatches terminate chain growth. However, the extent to which cPcdh interactions fulfill these requirements has not been definitively demonstrated. Here, we report biophysical experiments showing that cPcdh cis interactions are promiscuous, but with preferences favoring formation of heterologous cis dimers. Trans homophilic interactions are remarkably precise, with no evidence for heterophilic interactions between different isoforms. A new C-type cPcdh crystal structure and mutagenesis data help to explain these observations. Overall, the interaction characteristics we report for cPcdhs help explain their function in neuronal self-/nonself-discrimination.