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This is the Wikipedia entry entitled "Protocadherin". More...
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Protocadherin Edit Wikipedia article
Domain organization of different types of cadherins showing unique features of protocadherins :Extracellular domain is longer and intracellular domain lack attachment with cytoskeleton.
Protocadherins (Pcdhs) are the largest mammalian subgroup of the cadherin superfamily of homophilic cell-adhesion proteins. 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. 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. 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.
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 Î±, Î², Î³ 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.
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.
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. Like classical cadherins, members of Pcdhs family were also shown to mediate cell-cell adhesion in cell-based assays and most of them showed to engage in homophilic trans-interactions. Schreiner and Weiner  showed that PcdhÎ± and Î³ 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 The cytoplasmic domain also mediates intracellular retention, a property which distinguishes the clustered protocadherins from the related classical cadherins. Furthermore, it was shown that Pcdhs are proteolytically processed by Î³-secretase complex, 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, schizophrenia, and neurodegenerative diseases
- Neuronal self-avoidance
- Epileptic Encephalopathy, Early Infantile, 9, caused by mutation in the gene encoding protocadherin-19
- Hulpiau P, van Roy F (February 2009). "Molecular evolution of the cadherin superfamily". The International Journal of Biochemistry & Cell Biology. 41 (2): 349â€“69. doi:10.1016/j.biocel.2008.09.027. PMID 18848899.
- Sano K, Tanihara H, Heimark RL, Obata S, Davidson M, St John T, Taketani S, Suzuki S (June 1993). "Protocadherins: a large family of cadherin-related molecules in central nervous system". The EMBO Journal. 12 (6): 2249â€“56. doi:10.1002/j.1460-2075.1993.tb05878.x. PMC 413453. PMID 8508762.
- Chen WV, Alvarez FJ, Lefebvre JL, Friedman B, Nwakeze C, Geiman E, Smith C, Thu CA, Tapia JC, Tasic B, Sanes JR, Maniatis T (August 2012). "Functional significance of isoform diversification in the protocadherin gamma gene cluster". Neuron. 75 (3): 402â€“9. doi:10.1016/j.neuron.2012.06.039. PMC 3426296. PMID 22884324.
- Albertin, Caroline B.; Simakov, Oleg; Mitros, Therese; Wang, Z. Yan; Pungor, Judit R.; Edsinger-Gonzales, Eric; Brenner, Sydney; Ragsdale, Clifton W.; Rokhsar, Daniel S. (August 2015). "The octopus genome and the evolution of cephalopod neural and morphological novelties". Nature. 524 (7564): 220â€“224. Bibcode:2015Natur.524..220A. doi:10.1038/nature14668. ISSN 0028-0836. PMC 4795812. PMID 26268193.
- Chen WV, Maniatis T (August 2013). "Clustered protocadherins". Development. 140 (16): 3297â€“302. doi:10.1242/dev.090621. PMC 3737714. PMID 23900538.
- Kohmura N, Senzaki K, Hamada S, Kai N, Yasuda R, Watanabe M, Ishii H, Yasuda M, Mishina M, Yagi T (June 1998). "Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic complex". Neuron. 20 (6): 1137â€“51. doi:10.1016/s0896-6273(00)80495-x. PMID 9655502.
- Wang X, Weiner JA, Levi S, Craig AM, Bradley A, Sanes JR (December 2002). "Gamma protocadherins are required for survival of spinal interneurons". Neuron. 36 (5): 843â€“54. doi:10.1016/s0896-6273(02)01090-5. PMID 12467588.
- Kallenbach S, Khantane S, Carroll P, Gayet O, Alonso S, Henderson CE, Dudley K (June 2003). "Changes in subcellular distribution of protocadherin gamma proteins accompany maturation of spinal neurons". Journal of Neuroscience Research. 72 (5): 549â€“56. doi:10.1002/jnr.10618. PMID 12749019.
- Phillips GR, Tanaka H, Frank M, Elste A, Fidler L, Benson DL, Colman DR (June 2003). "Gamma-protocadherins are targeted to subsets of synapses and intracellular organelles in neurons". The Journal of Neuroscience. 23 (12): 5096â€“104. doi:10.1523/JNEUROSCI.23-12-05096.2003. PMID 12832533.
- Junghans D, Heidenreich M, Hack I, Taylor V, Frotscher M, Kemler R (February 2008). "Postsynaptic and differential localization to neuronal subtypes of protocadherin beta16 in the mammalian central nervous system". The European Journal of Neuroscience. 27 (3): 559â€“71. doi:10.1111/j.1460-9568.2008.06052.x. PMID 18279309.
- Obata S, Sago H, Mori N, Rochelle JM, Seldin MF, Davidson M, St John T, Taketani S, Suzuki ST (December 1995). "Protocadherin Pcdh2 shows properties similar to, but distinct from, those of classical cadherins". Journal of Cell Science. 108 ( Pt 12): 3765â€“73. PMID 8719883.
- Frank M, Ebert M, Shan W, Phillips GR, Arndt K, Colman DR, Kemler R (August 2005). "Differential expression of individual gamma-protocadherins during mouse brain development". Molecular and Cellular Neurosciences. 29 (4): 603â€“16. doi:10.1016/j.mcn.2005.05.001. PMID 15964765.
- Reiss K, Maretzky T, Haas IG, Schulte M, Ludwig A, Frank M, Saftig P (August 2006). "Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion". The Journal of Biological Chemistry. 281 (31): 21735â€“44. doi:10.1074/jbc.M602663200. PMID 16751190.
- Schreiner D, Weiner JA (August 2010). "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. 107 (33): 14893â€“8. doi:10.1073/pnas.1004526107. PMC 2930437. PMID 20679223.
- Schalm SS, Ballif BA, Buchanan SM, Phillips GR, Maniatis T (August 2010). "Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret". Proceedings of the National Academy of Sciences of the United States of America. 107 (31): 13894â€“9. doi:10.1073/pnas.1007182107. PMC 2922223. PMID 20616001.
- FernÃ¡ndez-Monreal M, Kang S, Phillips GR (March 2009). "Gamma-protocadherin homophilic interaction and intracellular trafficking is controlled by the cytoplasmic domain in neurons". Molecular and Cellular Neurosciences. 40 (3): 344â€“53. doi:10.1016/j.mcn.2008.12.002. PMC 2646808. PMID 19136062.
- Bonn S, Seeburg PH, Schwarz MK (June 2007). "Combinatorial expression of alpha- and gamma-protocadherins alters their presenilin-dependent processing". Molecular and Cellular Biology. 27 (11): 4121â€“32. doi:10.1128/MCB.01708-06. PMC 1900011. PMID 17403907.
- Buchanan SM, Schalm SS, Maniatis T (October 2010). "Proteolytic processing of protocadherin proteins requires endocytosis". Proceedings of the National Academy of Sciences of the United States of America. 107 (41): 17774â€“9. Bibcode:2010PNAS..10717774B. doi:10.1073/pnas.1013105107. PMC 2955128. PMID 20876099.
- Kaufmann WE, Moser HW (October 2000). "Dendritic anomalies in disorders associated with mental retardation". Cerebral Cortex. 10 (10): 981â€“91. doi:10.1093/cercor/10.10.981. PMID 11007549.
- Kalmady SV, Venkatasubramanian G (March 2009). "Evidence for positive selection on Protocadherin Y gene in Homo sapiens: implications for schizophrenia". Schizophrenia Research. 108 (1â€“3): 299â€“300. doi:10.1016/j.schres.2008.09.015. PMID 18938061.
- Anderton BH, Callahan L, Coleman P, Davies P, Flood D, Jicha GA, Ohm T, Weaver C (August 1998). "Dendritic changes in Alzheimer's disease and factors that may underlie these changes". Progress in Neurobiology. 55 (6): 595â€“609. doi:10.1016/s0301-0082(98)00022-7. PMID 9670220.
- Triana-Baltzer GB, Blank M (March 2006). "Cytoplasmic domain of protocadherin-alpha enhances homophilic interactions and recognizes cytoskeletal elements". Journal of Neurobiology. 66 (4): 393â€“407. doi:10.1002/neu.20228. PMID 16408303.
- Han MH, Lin C, Meng S, Wang X (January 2010). "Proteomics analysis reveals overlapping functions of clustered protocadherins". Molecular & Cellular Proteomics. 9 (1): 71â€“83. doi:10.1074/mcp.M900343-MCP200. PMC 2808268. PMID 19843561.
- Sotomayor M, Gaudet R, Corey DP (September 2014). "Sorting out a promiscuous superfamily: towards cadherin connectomics". Trends in Cell Biology. 24 (9): 524â€“36. doi:10.1016/j.tcb.2014.03.007. PMC 4294768. PMID 24794279.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Protocadherin Provide feedback
The structure of protocadherins is similar to that of classic cadherins (PF00028), but particularly on the cytoplasmic domains they also have some unique features. They are expressed in a variety of organisms and are found in high concentrations in the brain where they seem to be localised mainly at cell-cell contact sites. Their expression seems to be developmentally regulated .
Sano K, Tanihara H, Heimark RL, Obata S, Davidson M, St John T, Taketani S, Suzuki S; , EMBO J 1993;12:2249-2256.: Protocadherins: a large family of cadherin-related molecules in central nervous system. PUBMED:8508762 EPMC:8508762
Internal database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR013585
The structure of protocadherins is similar to that of classic cadherins (INTERPRO), but they also have some unique features associated with the cytoplasmic domains. They are expressed in a variety of organisms and are found in high concentrations in the brain where they seem to be localised mainly at cell-cell contact sites. Their expression seems to be developmentally regulated [PUBMED:8508762].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_4100 (release 18.0)|
|Number in seed:||17|
|Number in full:||658|
|Average length of the domain:||212.60 aa|
|Average identity of full alignment:||49 %|
|Average coverage of the sequence by the domain:||20.22 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||11|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.