Protocadherin

Protocadherin, cytoplasmic
Domain organization of different types of cadherins showing unique features of protocadherins: Extracellular domain is longer and intracellular domain lacks attachment with cytoskeleton.
Identifiers
Symbol	PDCH
Pfam	PF08374
InterPro	IPR013585
Membranome	114
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Protocadherins (Pcdhs) are the largest mammalian subgroup of the

In mammals, two types of Pcdh genes have been defined: the non-clustered Pcdhs which are scattered throughout the genome; and the clustered Pcdhs organized in three gene clusters designated α, β, γ which in mouse genome comprises 14, 22 and 22, respectively, large variable exons arrayed in tandem. Each exon is transcribed from its owner promoter and encodes: the entire extracellular domain, a transmembrane domain, and a short and variable intracellular domain of the corresponding Pcdh protein which differs from the Cadherin intracellular domain due to lack of attachment to the cytoskeleton through catenins.^[5]

Moreover, these clustered Pcdh genes are predominantly expressed in the developing nervous system^[2] and since different subsets of Pcdhs genes are differentially expressed in individual neurons, a vast cell surface diversity may arise from this combinatorial expression.^[5] This has led to speculation and further to the proposal that Pcdhs may provide a synaptic-address code for neuronal connectivity or a single-cell barcode for self-recognition/self-avoidance similar to that ascribed to DSCAM proteins of invertebrates. Although vertebrate DSCAMs lack the diversity of their invertebrate counterparts, the selective transcription of individual Pcdh isoforms can be achieved by promoter choice followed by alternative pre-mRNA cis-splicing thus increasing the number of possible combinations.

Function

Homophilic interactions and intracellular signaling

Clustered Pcdhs proteins are detected throughout the neuronal soma, dendrites and axons and are observed in synapses and growth cones.^{[6][7][8][9][10]} Like classical cadherins, members of Pcdhs family were also shown to mediate cell-cell adhesion in cell-based assays^[11][12][13] and most of them showed to engage in homophilic trans-interactions.^[14] Schreiner and Weiner ^[14] showed that Pcdhα and γ proteins can form multimeric complexes. If all three classes of Pcdhs could engage in multimerization of stochastically expressed Pcdhs isoforms, then neurons could produce a large number of distinct homophilic interaction units, amplifying significantly the cell-surface diversity more than the one afforded by stochastic gene expression alone.

As for cytoplasmic domain, all the three classes of clustered Pcdhs proteins are dissimilar, although they are strictly conserved in vertebrate evolution, suggesting a conserved cellular function.

The cytoplasmic domain of Pcdh-alpha can be divided into two specific types. Both of them enhance homophilic interactions. They associate with neurofillament M and fascin respectively.^[22]

Human genes

See also

• Cadherin
• PCDH11X
• Neuronal self-avoidance
• Epileptic Encephalopathy, Early Infantile, 9
  , caused by mutation in the gene encoding protocadherin-19

References