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 (Nickerson et al., 2002). FLCN is also observed to be phosphorylated, and further details regarding this modification can be found in Folliculin-binding proteins: Interactions with FLCN.
Two other FLCN isoforms are also predicted, produced by alternative splicing. These lack the C-terminal end and are 342 and 197 amino acids in length (Nickerson et al., 2002). These proteins are similar to the yeast FLCN homologue, LST7, which only contains the N-terminal part of the protein. If the truncated FLCN produced by gene mutations remains in the cell, it could have a similar function to the FLCN isoforms.
The protein sequence of the primary FLCN isoform is as follows:
MNAIVALCHFCELHGPRTLFCTEVLHAPLPQGDGNEDSPGQGEQAEEEEGGIQMNSRMRAHSPAE
GASVESSSPGPKKSDMCEGCRSLAAGHPGYISHDKETSIKYVSHQHPSHPQLFSIVRQACVRSLSCEV
CPGREGPIFFGDEQHGFVFSHTFFIKDSLARGFQRWYSIITIMMDRIYLINSWPFLLGKVRGIIDELQGK
ALKVFEAEQFGCPQRAQRMNTAFTPFLHQRNGNAARSLTSLTSDDNLWACLHTSFAWLLKACGSR
LTEKLLEGAPTEDTLVQMEKLADLEEESESWDNSEAEEEEKAPVLPESTEGRELTQGPAESSSLSG
CGSWQPRKLPVFKSLRHMRQVLGAPSFRMLAWHVLMGNQVIWKSRDVDLVQSAFEVLRTMLPVG
CVRIIPYSSQYEEAYRCNFLGLSPHVQIPPHVLSSEFAVIVEVHAAARSTLHPVGCEDDQSLSKYEFVV
TSGSPVAADRVGPTILNKIEAALTNQNLSVDVVDQCLVCLKEEWMNKVKVLFKFTKVDSRPKEDTQ
KLLSILGASEEDNVKLLKFWMTGLSKTYKSHLMSTVRSPTASESRN
List of amino acids, their abbreviations and details.
No transmembrane domains or organelle localisation signals have been determined within the FLCN sequence (Warren et al., 2004). FLCN has no significant homology to any known protein, but it is highly conserved across species including Canis lupus familiaris, Bos Taurus, Mus musculus, Rattus norvegicus, Gallus gallus, Xenopus tropicalis, and Drosophila melanogaster, suggesting an important biological role (Nickerson et al., 2002). A sequence alignment shows this conservation.
Warren et al. (2004) studied the expression of FLCN mRNA in both normal and neoplastic human tissue and found that in normal cells FLCN was 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, epithelial ducts of the breast and prostate, areas of the brain and in macrophages and lymphocytes in the tonsils and spleen. Tissues with no FLCN mRNA expression included the heart, muscle and liver (Warren et al., 2004). The fact that FLCN mRNA is not detected in BHD-associated renal tumours provides further evidence supporting the idea that FLCN is a tumour suppressor.
Hudon et al. (2010) characterised the tissue distribution of mouse FLCN. It was found to have a similar distribution to the human FLCN, with high expression levels in the kidneys, lungs and spleen. Interestingly, no Flcn expression was seen in the murine skin, correlating with the lack of skin lesions in FLCN-null mice.
For details on FLCN cellular localisation, click here.
