5. Folliculin expression
FLCN is predicted to encode the 579 amino acid protein FLCN (64kDa), consisting of a short hydrophobic N-terminal sequence, one N-glycosylation site, three myristoylation sites and a glutamic acid-rich coiled coil domain centrally located in the protein. FLCN protein sequence is as follows:
MNAIVALCHFCELHGPRTLFCTEVLHAPLPQGDGNEDSPGQGEQAEEEEGGIQMNSRMRAHSPAEGASV
ESSSPGPKKSDMCEGCRSLAAGHPGYISHDKETSIKYVSHQHPSHPQLFSIVRQACVRSLSCEVCPGREGP
IFFGDEQHGFVFSHTFFIKDSLARGFQRWYSIITIMMDRIYLINSWPFLLGKVRGIIDELQGKALKVFEA
EQFGCPQRAQRMNTAFTPFLHQRNGNAARSLTSLTSDDNLWACLHTSFAWLLKACGSRLTEKLLEGAPTE
DTLVQMEKLADLEEESESWDNSEAEEEEKAPVLPESTEGRELTQGPAESSSLSGCGSWQPRKLPVFKSLR
HMRQVLGAPSFRMLAWHVLMGNQVIWKSRDVDLVQSAFEVLRTMLPVGCVRIIPYSSQYEEAYRCNFLGL
SPHVQIPPHVLSSEFAVIVEVHAAARSTLHPVGCEDDQSLSKYEFVVTSGSPVAADRVGPTILNKIEAAL
TNQNLSVDVVDQCLVCLKEEWMNKVKVLFKFTKVDSRPKEDTQKLLSILGASEEDNVKLLKFWMTGLSKT
YKSHLMSTVRSPTASESRN
Protein Key:
| G | Glycine | Gly | P | Proline | Pro | ||||||||||||
| A | Alanine | Ala | V | Valine | Val | ||||||||||||
| L | Leucine | Leu | I | Isoleucine | Ile | ||||||||||||
| M | Methionine | Met | C | Cysteine | Cys | ||||||||||||
| F | Phenylalanine | Phe | Y | Tyrosine | Tyr | ||||||||||||
| W | Tryptophan | Trp | H | Histidine | His | ||||||||||||
| K | Lysine | Lys | R | Arginine | Arg | ||||||||||||
| Q | Glutamine | Gln | N | Asparagine | Asn | ||||||||||||
| E | Glutamic Acid | Glu | D | Aspartic Acid | Asp | ||||||||||||
| S | Serine | Ser | T | Threonine | Thr |
No transmembrane domains or organelle localization signals have been determined as yet (Warren et al, 2004). FLCN has no significant homology to any known protein, but is highly conserved across species including Drosophila melanogaster, Xenopus tropicalis, Mus musculus, Rattus norvegicus, Caenorhabditis elegans, Canis lupus familiaris, Bos Taurus, Gallus gallus, Macaca mulatta and Pan troglodytes, suggesting an important biological role (Nickerson et al, 2002).
FLCN mRNA is expressed in: the skin; the distal nephron of the kidney; stromal cells and type 1 pneumocytes of the lung; acinar cells of the pancreas and parotid gland; and epithelial ducts of the breast and prostate. In the brain, FLCN mRNA is expressed in neurons of the cerebrum, and Purkinje cells in the cerebellum. FLCN mRNA is also detectable in macrophage and lymphocytes in the tonsils and spleen. Tissues with lower levels of FLCN mRNA included heart, muscle and liver (Warren et al, 2004). Further evidence supporting the tumour suppressor function of FLCN in renal cancer is that FLCN mRNA is not detected in renal tumours from BHD patients. Localisation of FLCN to both the nucleus and cytoplasm was determined by fluorescence in situ hybridization using epitope-tagged FLCN expressed in HEK293 cells (Baba et al, 2006).
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