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0  structures 1095  species 0  interactions 2303  sequences 37  architectures

Family: CLN3 (PF02487)

Summary: CLN3 protein

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CLN3 protein Provide feedback

This is a family of proteins from the CLN3 gene. A mis-sense 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]. Batten disease is characterised by the accumulation of autofluorescent material in the lysosomes of most cells. Members of this family are transmembrane proteins functional in pre-vacuolar compartments. The protein in Sch.pombe is found to be localised to the vacuolar membrane, and a lack of functional protein clearly affects the size and pH of the vacuole. Thus the protein is necessary for vacuolar homeostasis [2]. It is important for localisation of late endosomal/lysosomal compartments, and it interacts with motor components driving both plus and minus end microtubular trafficking: tubulin, dynactin, dynein and kinesin-2 [3].

Literature references

  1. 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 EPMC:9490299

  2. Gachet Y, Codlin S, Hyams JS, Mole SE;, J Cell Sci. 2005;118:5525-5536.: btn1, the Schizosaccharomyces pombe homologue of the human Batten disease gene CLN3, regulates vacuole homeostasis. PUBMED:16291725 EPMC:16291725

  3. Uusi-Rauva K, Kyttala A, van der Kant R, Vesa J, Tanhuanpaa K, Neefjes J, Olkkonen VM, Jalanko A;, Cell Mol Life Sci. 2012;69:2075-2089.: Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments. PUBMED:22261744 EPMC:22261744

Internal database links

This tab holds annotation information from the InterPro database.

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.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan MFS (CL0015), which has the following description:

The major facilitator superfamily (MFS) is one of the two largest families of membrane transporters found on Earth [1]. It is present ubiquitously in bacteria, archaea, and eukarya and includes members that can function by solute uniport, solute/cation symport, solute/cation antiport and/or solute/solute antiport with inwardly and/or outwardly directed polarity [1]. All permeases of the MFS possess either 12 or 14 transmembrane helices [1].

The clan contains the following 26 members:

Acatn ATG22 BT1 CLN3 DUF5690 Folate_carrier FPN1 LacY_symp MFS_1 MFS_1_like MFS_2 MFS_3 MFS_4 MFS_5 MFS_Mycoplasma Nodulin-like Nuc_H_symport Nucleoside_tran OATP PTR2 PUCC Sugar_tr TLC TRI12 UNC-93 UVB_sens_prot


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Curation View help on the curation process

Seed source: Pfam-B_1060 (release 5.4)
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Mian N , Bateman A
Number in seed: 88
Number in full: 2303
Average length of the domain: 300.00 aa
Average identity of full alignment: 31 %
Average coverage of the sequence by the domain: 80.20 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 31.0 31.0
Trusted cut-off 31.1 31.1
Noise cut-off 29.7 30.5
Model length: 394
Family (HMM) version: 20
Download: download the raw HMM for this family

Species distribution

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trRosetta Structure

The structural model below was generated by the Baker group with the trRosetta software using the Pfam UniProt multiple sequence alignment.

The InterPro website shows the contact map for the Pfam SEED alignment. Hovering or clicking on a contact position will highlight its connection to other residues in the alignment, as well as on the 3D structure.

Improved protein structure prediction using predicted inter-residue orientations. Jianyi Yang, Ivan Anishchenko, Hahnbeom Park, Zhenling Peng, Sergey Ovchinnikov, David Baker Proceedings of the National Academy of Sciences Jan 2020, 117 (3) 1496-1503; DOI: 10.1073/pnas.1914677117;