Summary

CLN3 protein

This is a family of proteins from the CLN3 gene. A missense mutation of glutamic acid (E) to lysine (K) at position 295 in the human protein (Q13286) has been implicated in Juvenile neuronal ceroid lipofuscinosis (Batten disease) [1].

Literature references

Zhong N, Wisniewski KE, Kaczmarski AL, Ju W, Xu WM, Xu WW, Mclendon L, Liu B, Kaczmarski W, Sklower Brooks SS, Brown WT; , Hum Genet 1998;102:57-62.: Molecular screening of Batten disease: identification of a missense mutation (E295K) in the CLN3 gene. PUBMED:9490299

InterPro entry IPR003492

Batten's disease, the juvenile variant of neuronal ceroid lipofuscionosis (NCL), is a recessively inherited disorder affecting children of 5-10 years of age. The disease is characterised by progressive loss of vision, seizures and psychomotor disturbances. Biochemically, the disease is characterised by lysosomal accumulation of hydrophobic material, mainly ATP synthase subunit C, largely in the brain but also in other tissues. The disease is fatal within a decade PUBMED:7553855.

Mutations in the CLN3 gene are believed to cause Batten's disease PUBMED:7553855. The CLN3 gene, with a predicted 438-residue product, maps to chromosome p16p12.1. The gene contains at least 15 exons spanning 15kb and is highly conserved in mammals PUBMED:2142158. A 1.02kb deletion in the CLN3 gene, occurring in either one or both alleles, is found in 85% of Batten disease chromosomes causing a frameshift generating a predicted translated product of 181 amino acid residues PUBMED:7553855, PUBMED:10191115. 22 other mutations, including deletions, insertions and point mutations, have been reported. It has been suggested that such mutations result in severely truncated CLN3 proteins, or affect its structure/conformation PUBMED:7553855, PUBMED:9311735.

CLN3 proteins, which are believed to associate in complexes, are heavily glycosylated lysosomal membrane proteins PUBMED:10191115, containing complex Asn-linked oligosaccharides PUBMED:2142158. Extensive glycosylation is important for the stability of these lysosomal proteins in the highly hydrolytic lysosomal lumen. Lysosomal sequestration of active lysosomal enzymes, transport of degraded molecules from the lysosomes, and fusion and fission between lysosomes and other organelles. The CLN3 protein is a 43kDa, highly hydrophobic, multi-transmembrane (TM), phosphorylated protein PUBMED:10191115. Hydrophobicity analysis predicts 6-9 TM segments, suggesting that CLN3 is a TM protein that may function as a chaperone or signal transducer. The majority of putative phosphorylation sites are found in the N-terminal domain, encompassing 150 residues PUBMED:10191114. Phosphorylation is believed to be important for membrane compartment interaction, in the formation of functional complexes, and in regulation and interactions with other proteins PUBMED:1482112.

CLN3 contains several motifs that may undergo lipid post-translational modifications (PTMs). PTMs contribute to targeting and anchoring of modified proteins to distinct biological membranes PUBMED:7716512. There are three general classes of lipid modification: N-terminal myristoylation, C-terminal prenylation, and palmitoylation of cysteine residues. Such modifications are believed to be a common form of PTM occurring in 0.5% of all cellular proteins, including brain tissue PUBMED:10191112. The C terminus of the CLN3 contains various lipid modification sites: C435, target for prenylation; G419, target for myristoylation; and C414, target for palmitoylation PUBMED:9384607. Prenylation results in protein hydrophobicity, influences interaction with upstream regulatory proteins and downstream effectors, facilitates protein-protein interaction (multisubunit assembly) and promotes anchoring to membrane lipids. The prenylation motif, Cys-A-A-X, is highly conserved within CLN3 protein sequences of different species PUBMED:10191112. Species with known CLN3 protein homologues include: Homo sapiens, Canis familiaris, Mus musculus, Saccharomyces cerevisiae and Drosophila melanogaster.

Clan

This family is a member of clan MFS (CL0015), which contains the following 22 members:

ATG22 BT1 CLN3 DUF1228 DUF791 DUF894 Folate_carrier FPN1 FTR1 LacY_symp MFS_1 MFS_Mycoplasma Nodulin-like Nuc_H_symport Nucleoside_tran OATP PTR2 PUCC Sugar_tr TLC TRI12 UNC-93

Gene Ontology

Cellular component

membrane (GO:0016020)

External database links

PANDIT:	PF02487
SYSTERS:	CLN3

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

View options

Alignment:	Seed (5) Full (203) NCBI (313) Metagenomics (12)
Viewer:

Formatting options

Alignment:	Seed (5) Full (203)
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

Pfam alignments:	Seed (5) Full (203) NCBI (313) Metagenomics (12)
Full length sequences	Full-sequences (203)

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER2.

HMM logo

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...

Trees

This page displays the phylogenetic tree for this family. 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 or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

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.

Curation

Seed source:

Pfam-B_1060 (release 5.4)

Previous IDs:

none

Type:

Family

Author:

Mian N, Bateman A

Number in seed:

5

Number in full:

203

Average length of the domain:

295.90 aa

Average identity of full alignment:

28 %

Average coverage of the sequence by the domain:

71.64 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 9421015 -E 1000 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	19.3	19.3
Trusted cut-off	20.1	19.8
Noise cut-off	19.2	18.9

Model length:

409

Family (HMM) version:

10

Download:

download the raw HMM for this family

Species distribution

Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

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.

Interactive tree

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

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Family: CLN3 (PF02487)

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