Protocadherin

{{Infobox protein family

| Symbol = PDCH

| Name = Protocadherin, cytoplasmic

| image = Protocadherins image2.png

| width = 300px

| caption = Domain organization of different types of cadherins showing unique features of protocadherins: Extracellular domain is longer and intracellular domain lacks attachment with cytoskeleton.

| Pfam = PF08374

| Pfam_clan =

| InterPro = IPR013585

| SMART =

| PROSITE =

| MEROPS =

| SCOP =

| TCDB =

| OPM family =

| OPM protein =

| CAZy =

| CDD =

| Membranome superfamily = 114

}}

Protocadherins (Pcdhs) are the largest mammalian subgroup of the cadherin superfamily of homophilic cell-adhesion proteins.{{cite journal | vauthors = Hulpiau P, van Roy F | title = Molecular evolution of the cadherin superfamily | journal = The International Journal of Biochemistry & Cell Biology | volume = 41 | issue = 2 | pages = 349–69 | date = February 2009 | pmid = 18848899 | doi = 10.1016/j.biocel.2008.09.027 }} They were discovered by Shintaro Suzuki's group, when they used PCR to find new members of the cadherin family. The PCR fragments that corresponded to protocadherins were found in vertebrate and invertebrate species.{{cite journal | vauthors = Sano K, Tanihara H, Heimark RL, Obata S, Davidson M, St John T, Taketani S, Suzuki S | title = Protocadherins: a large family of cadherin-related molecules in central nervous system | journal = The EMBO Journal | volume = 12 | issue = 6 | pages = 2249–56 | date = June 1993 | pmid = 8508762 | pmc = 413453 | doi = 10.1002/j.1460-2075.1993.tb05878.x }} This prevalence in a wide range of species suggested that the fragments were part of an ancient cadherin and were thus termed "Protocadherins" as the "first cadherins". Of the approximately 70 Pcdh genes identified in mammalian genomes, over 50 are located in tightly linked gene clusters on the same chromosome.{{cite journal | vauthors = Chen WV, Alvarez FJ, Lefebvre JL, Friedman B, Nwakeze C, Geiman E, Smith C, Thu CA, Tapia JC, Tasic B, Sanes JR, Maniatis T | title = Functional significance of isoform diversification in the protocadherin gamma gene cluster | journal = Neuron | volume = 75 | issue = 3 | pages = 402–9 | date = August 2012 | pmid = 22884324 | pmc = 3426296 | doi = 10.1016/j.neuron.2012.06.039 }} Until recently, it was assumed that this kind of organization can only be found in vertebrates, but Octopus bimaculoides has 168 genes of which nearly three-quarters are found in tandem clusters with the two largest clusters compromising 31 and 17 genes, respectively.{{Cite journal|last1=Albertin|first1=Caroline B.|last2=Simakov|first2=Oleg|last3=Mitros|first3=Therese|last4=Wang|first4=Z. Yan|last5=Pungor|first5=Judit R.|last6=Edsinger-Gonzales|first6=Eric|last7=Brenner|first7=Sydney|last8=Ragsdale|first8=Clifton W.|last9=Rokhsar|first9=Daniel S.|date=August 2015|title=The octopus genome and the evolution of cephalopod neural and morphological novelties|journal=Nature|volume=524|issue=7564|pages=220–224|doi=10.1038/nature14668|issn=0028-0836|pmc=4795812|pmid=26268193|bibcode=2015Natur.524..220A}}

Classification

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.{{cite journal | vauthors = Chen WV, Maniatis T | title = Clustered protocadherins | journal = Development | volume = 140 | issue = 16 | pages = 3297–302 | date = August 2013 | pmid = 23900538 | pmc = 3737714 | doi = 10.1242/dev.090621 }}

Moreover, these clustered Pcdh genes are predominantly expressed in the developing nervous system and since different subsets of Pcdhs genes are differentially expressed in individual neurons, a vast cell surface diversity may arise from this combinatorial expression. 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.{{cite journal | vauthors = Kohmura N, Senzaki K, Hamada S, Kai N, Yasuda R, Watanabe M, Ishii H, Yasuda M, Mishina M, Yagi T | title = Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic complex | journal = Neuron | volume = 20 | issue = 6 | pages = 1137–51 | date = June 1998 | pmid = 9655502 | doi = 10.1016/s0896-6273(00)80495-x | doi-access = free }}{{cite journal | vauthors = Wang X, Weiner JA, Levi S, Craig AM, Bradley A, Sanes JR | title = Gamma protocadherins are required for survival of spinal interneurons | journal = Neuron | volume = 36 | issue = 5 | pages = 843–54 | date = December 2002 | pmid = 12467588 | doi = 10.1016/s0896-6273(02)01090-5 | doi-access = free }}{{cite journal | vauthors = Kallenbach S, Khantane S, Carroll P, Gayet O, Alonso S, Henderson CE, Dudley K | title = Changes in subcellular distribution of protocadherin gamma proteins accompany maturation of spinal neurons | journal = Journal of Neuroscience Research | volume = 72 | issue = 5 | pages = 549–56 | date = June 2003 | pmid = 12749019 | doi = 10.1002/jnr.10618 | s2cid = 41159576 }}{{cite journal | vauthors = Phillips GR, Tanaka H, Frank M, Elste A, Fidler L, Benson DL, Colman DR | title = Gamma-protocadherins are targeted to subsets of synapses and intracellular organelles in neurons | journal = The Journal of Neuroscience | volume = 23 | issue = 12 | pages = 5096–104 | date = June 2003 | pmid = 12832533 | doi = 10.1523/JNEUROSCI.23-12-05096.2003 | pmc = 6741188 | doi-access = free }}{{cite journal | vauthors = Junghans D, Heidenreich M, Hack I, Taylor V, Frotscher M, Kemler R | title = Postsynaptic and differential localization to neuronal subtypes of protocadherin beta16 in the mammalian central nervous system | journal = The European Journal of Neuroscience | volume = 27 | issue = 3 | pages = 559–71 | date = February 2008 | pmid = 18279309 | doi = 10.1111/j.1460-9568.2008.06052.x | s2cid = 24229102 }} Like classical cadherins, members of Pcdhs family were also shown to mediate cell-cell adhesion in cell-based assays{{cite journal | vauthors = Obata S, Sago H, Mori N, Rochelle JM, Seldin MF, Davidson M, St John T, Taketani S, Suzuki ST | title = Protocadherin Pcdh2 shows properties similar to, but distinct from, those of classical cadherins | journal = Journal of Cell Science | volume = 108 ( Pt 12) | pages = 3765–73 | date = December 1995 | issue = 12 | doi = 10.1242/jcs.108.12.3765 | pmid = 8719883 }}{{cite journal | vauthors = Frank M, Ebert M, Shan W, Phillips GR, Arndt K, Colman DR, Kemler R | title = Differential expression of individual gamma-protocadherins during mouse brain development | journal = Molecular and Cellular Neurosciences | volume = 29 | issue = 4 | pages = 603–16 | date = August 2005 | pmid = 15964765 | doi = 10.1016/j.mcn.2005.05.001 | s2cid = 40074917 }}{{cite journal | vauthors = Reiss K, Maretzky T, Haas IG, Schulte M, Ludwig A, Frank M, Saftig P | title = Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion | journal = The Journal of Biological Chemistry | volume = 281 | issue = 31 | pages = 21735–44 | date = August 2006 | pmid = 16751190 | doi = 10.1074/jbc.M602663200 | doi-access = free }} and most of them showed to engage in homophilic trans-interactions.{{cite journal | vauthors = Schreiner D, Weiner JA | title = Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 33 | pages = 14893–8 | date = August 2010 | pmid = 20679223 | pmc = 2930437 | doi = 10.1073/pnas.1004526107 | bibcode = 2010PNAS..10714893S | doi-access = free }} Schreiner and Weiner 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. This is corroborated by a large number of other interacting proteins including phosphatases, kinases, adhesion molecules and synaptic proteins{{cite journal | vauthors = Schalm SS, Ballif BA, Buchanan SM, Phillips GR, Maniatis T | title = Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 31 | pages = 13894–9 | date = August 2010 | pmid = 20616001 | pmc = 2922223 | doi = 10.1073/pnas.1007182107 | doi-access = free }} The cytoplasmic domain also mediates intracellular retention, a property which distinguishes the clustered protocadherins from the related classical cadherins.{{cite journal | vauthors = Fernández-Monreal M, Kang S, Phillips GR | title = Gamma-protocadherin homophilic interaction and intracellular trafficking is controlled by the cytoplasmic domain in neurons | journal = Molecular and Cellular Neurosciences | volume = 40 | issue = 3 | pages = 344–53 | date = March 2009 | pmid = 19136062 | pmc = 2646808 | doi = 10.1016/j.mcn.2008.12.002 }} Furthermore, it was shown that Pcdhs are proteolytically processed by γ-secretase complex,{{cite journal | vauthors = Bonn S, Seeburg PH, Schwarz MK | title = Combinatorial expression of alpha- and gamma-protocadherins alters their presenilin-dependent processing | journal = Molecular and Cellular Biology | volume = 27 | issue = 11 | pages = 4121–32 | date = June 2007 | pmid = 17403907 | pmc = 1900011 | doi = 10.1128/MCB.01708-06 }}{{cite journal | vauthors = Buchanan SM, Schalm SS, Maniatis T | title = Proteolytic processing of protocadherin proteins requires endocytosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 41 | pages = 17774–9 | date = October 2010 | pmid = 20876099 | pmc = 2955128 | doi = 10.1073/pnas.1013105107 | bibcode = 2010PNAS..10717774B | doi-access = free }} which releases soluble intracellular fragments into the cytoplasm which might have a broad range of functions as acting locally in the cytoplasm and/or even regulate gene expression similarly to other cell-surface proteins such as Notch and N-cadherin.

Since these molecules are involved in so many developmental processes like axon guidance and dendrite arborization, mutations in Pcdhs genes and their expression may play a role in Down, Rett as well as Fragile X syndrome,{{cite journal | vauthors = Kaufmann WE, Moser HW | title = Dendritic anomalies in disorders associated with mental retardation | journal = Cerebral Cortex | volume = 10 | issue = 10 | pages = 981–91 | date = October 2000 | pmid = 11007549 | doi = 10.1093/cercor/10.10.981 | doi-access = free }} schizophrenia,{{cite journal | vauthors = Kalmady SV, Venkatasubramanian G | title = Evidence for positive selection on Protocadherin Y gene in Homo sapiens: implications for schizophrenia | journal = Schizophrenia Research | volume = 108 | issue = 1–3 | pages = 299–300 | date = March 2009 | pmid = 18938061 | doi = 10.1016/j.schres.2008.09.015 | s2cid = 26590444 }} and neurodegenerative diseases{{cite journal | vauthors = Anderton BH, Callahan L, Coleman P, Davies P, Flood D, Jicha GA, Ohm T, Weaver C | title = Dendritic changes in Alzheimer's disease and factors that may underlie these changes | journal = Progress in Neurobiology | volume = 55 | issue = 6 | pages = 595–609 | date = August 1998 | pmid = 9670220 | doi = 10.1016/s0301-0082(98)00022-7 | s2cid = 11421820 | doi-access = free }}

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.{{cite journal |vauthors=Triana-Baltzer GB, Blank M |title=Cytoplasmic domain of protocadherin-alpha enhances homophilic interactions and recognizes cytoskeletal elements. |journal=Journal of Neurobiology |date=March 2006 |volume=66 |issue=4 |pages=393–407 |doi=10.1002/neu.20228 |pmid=16408303}}

Human genes

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Protocadherin

Classification

Function

=Homophilic interactions and intracellular signaling=

Human genes

See also

References

Further reading