Occludin

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Occludin
Occludin.png
PDB, Structure of the Colied-coil domain of human Occludin(aa. 416-522)
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols OCLN ; BLCPMG
External IDs OMIM602876 MGI106183 HomoloGene1905 GeneCards: OCLN Gene
EC number 2.1.1.67
Orthologs
Species Human Mouse
Entrez 100506658 18260
Ensembl ENSG00000197822 ENSMUSG00000021638
UniProt Q16625 Q61146
RefSeq (mRNA) NM_001205254 NM_008756
RefSeq (protein) NP_001192183 NP_032782
Location (UCSC) Chr 5:
68.79 – 68.85 Mb
Chr 13:
100.5 – 100.55 Mb
PubMed search [1] [2]

Occludin is a protein that in humans is encoded by the OCLN gene.[1][2] Occludin is a 65-kDa (522-amino acid polypeptide -human) integral plasma-membrane protein located at the tight junctions, described for the first time in 1993 by Shoichiro Tsukita.[3] Together with the Claudin group of proteins, it is the main component of the tight junctions.

Gene Location[edit]

The OCLN gene is located on the long (q) arm of chromosome 5 at position q13.1. The gene starts at base pair 69,492,292 and goes to base pair 69,558,104 and is 65,813 base pairs long.[4]

Protein Structure[edit]

Occludin's structure can be broken down into 9 domains. These domains are separated into two groups. 5 of the domains are located intracellularly and extracellularly. These 5 domains are separated by the 4 transmembrane domains of the protein. The nine domains are as follows:

  • N-terminus domain (66 aa)
  • transmembrane domain 1 (23 aa)
  • extracellular loop 1 (46 aa)
  • transmembrane domain 2 (25 aa)
  • intracellular loop (10 aa)
  • transmembrane domain 3 (25 aa)
  • extracellular domain 2 (48 aa)
  • transmembrane domain 4 (22 aa)
  • C-terminus domain (257 aa)

The C-terminus domain has been shown experimentally to be required for correct assembly of tight junction barrier function.[5] The C-terminus also interacts with several cytoplasmic proteins of the junctional plaque and interacts with signaling molecules responsible for cell survival.[6] The N-terminus of occludin experimentally has been linked to involvement in tight junction sealing/barrier properties.[6] The extracellular loops are thought to be involved in the regulation of paracellualr permeability and the second extracellular has been shown to be involved in the localization of occludin at the tight junction.[6]

Function[edit]

Occludin is an important protein in tight junction function. Studies have shown that rather than being important in tight junction assembly, occludin is important in tight junction stability and barrier function. Furthermore, studies in which mice were deprived of occludin expression showed morphological stability in several epithelial tissues but also found chronic inflammation and hyperplasia in the gastric epithelium, calcification in the brain, testicular atrophy, loss of cytoplasmic granules in straited duct cells of salivary gland, and thinning of the compact bone. The phenotypical response of these mice to the lack of occludin suggest that the function of occludin is more complex than thought and requires more work.[7]

Role in Cancer[edit]

Occludin plays a critical role in maintaining the barrier properties of a tight junction. Thus, mutation or absence of occludin increases epithelial leakiness which is an important barrier in preventing metastasis of cancer. Loss of occludin or abnormal expression of occludin has been shown to cause increased invasion, reduced adhesion and significantly reduced tight junction function in breast cancer tissues. Furthermore, patients with metastatic disease displayed significantly lower levels of occludin suggesting that the loss of occludin and thereby loss of tight junction integrity is important in metastatic development of breast cancer.[8]

Occludin also plays an important role in the apoptosis. The C-terminus of occludin is important in receiving and transmitting cell survival signals. In standard cells, loss or disruption of occludin and other tight junction proteins leads to initiation of apoptosis through extrinsic pathways.[9] Studies involving high levels of expression of occludin in cancer cells have shown that occludin mitigates several important cancer proliferation properties. The presence of occludin decreased cellular invasiveness and motility, enhanced cellular sensitivity to apoptogenic factors and lowered tumorigenesis and metastasis of the cancer cells. Specifically, occludin has a strong inhibitory effect on Raf1-induced tumorigenesis. Still, the exact mechanism of how occludin prevents the progression of cancer is not known but it has been shown that cancer progression is linked to the loss of occludin or the silencing of the OCLN gene.[10]

Disease linkage[edit]

Disruption of occludin regulation is an important aspect of a number of diseases. Strategies to prevent and/or reverse occludin downregulation may be an important therapeutic target. Mutation of occludin are thought to be a cause of band-like calcification with simple gyration and polymicrogyria(BLC-PMG). BLC-PMG is an autosomal recessive neurologic disorder.

Diagram of Tight junction.

Interactions[edit]

Occludin has been shown to interact with Tight junction protein 2,[11][12][13] YES1[14] and Tight junction protein 1.[15][16]

References[edit]

  1. ^ Ando-Akatsuka Y, Saitou M, Hirase T, Kishi M, Sakakibara A, Itoh M, Yonemura S, Furuse M, Tsukita S (May 1996). "Interspecies diversity of the occludin sequence: cDNA cloning of human, mouse, dog, and rat-kangaroo homologues". J Cell Biol 133 (1): 43–47. doi:10.1083/jcb.133.1.43. PMC 2120780. PMID 8601611. 
  2. ^ "Entrez Gene: OCLN occludin". 
  3. ^ Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1993). "Occludin: a novel integral membrane protein localizing at tight junctions". J. Cell Biol. 123 (6 Pt 2): 1777–1788. doi:10.1083/jcb.123.6.1777. PMC 2290891. PMID 8276896. 
  4. ^ http://www.ncbi.nlm.nih.gov/gene/100506658
  5. ^ Chen Y, Merzdorf C, Paul DL, Goodenough DA. 1997. COOH terminus of occludin is required for tight junction barrier function in early Xenopus embryos. J. Cell Biol. 138:891–899
  6. ^ a b c Feldman, Gemma J., James M. Mullin, and Michael P. Ryan. "Occludin: structure, function and regulation." Advanced drug delivery reviews 57.6 (2005): 883-917.
  7. ^ Saitou, M. et al. 2000. Complex phenotype of micelacking occludin, a component of tight junctionstrands. Mol. Biol. Cell 11: 4131–4142.
  8. ^ Martin, Tracey A., Robert E. Mansel, and Wen G. Jiang. "Loss of occludin leads to the progression of human breast cancer." International journal of molecular medicine 26.5 (2010): 723-734.
  9. ^ Beeman, N., P. G. Webb, and H. K. Baumgartner. "Occludin is required for apoptosis when claudin–claudin interactions are disrupted." Cell death & disease 3.2 (2012): e273.
  10. ^ Osanai, Makoto, et al. "Epigenetic silencing of occludin promotes tumorigenic and metastatic properties of cancer cells via modulations of unique sets of apoptosis-associated genes." Cancer research 66.18 (2006): 9125-9133.
  11. ^ Peng, Bi-Hung; Lee J Ching; Campbell Gerald A (Dec 2003). "In vitro protein complex formation with cytoskeleton-anchoring domain of occludin identified by limited proteolysis". J. Biol. Chem. (United States) 278 (49): 49644–49651. doi:10.1074/jbc.M302782200. ISSN 0021-9258. PMID 14512431. 
  12. ^ Itoh, M; Morita K; Tsukita S (Feb 1999). "Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and alpha catenin". J. Biol. Chem. (UNITED STATES) 274 (9): 5981–5986. doi:10.1074/jbc.274.9.5981. ISSN 0021-9258. PMID 10026224. 
  13. ^ Wittchen, E S; Haskins J; Stevenson B R (Dec 1999). "Protein interactions at the tight junction. Actin has multiple binding partners, and ZO-1 forms independent complexes with ZO-2 and ZO-3". J. Biol. Chem. (UNITED STATES) 274 (49): 35179–35185. doi:10.1074/jbc.274.49.35179. ISSN 0021-9258. PMID 10575001. 
  14. ^ Chen, Yan-Hua; Lu Qun; Goodenough Daniel A; Jeansonne Beverly (Apr 2002). "Nonreceptor tyrosine kinase c-Yes interacts with occludin during tight junction formation in canine kidney epithelial cells". Mol. Biol. Cell (United States) 13 (4): 1227–1237. doi:10.1091/mbc.01-08-0423. ISSN 1059-1524. PMC 102264. PMID 11950934. 
  15. ^ Fanning, A S; Jameson B J; Jesaitis L A; Anderson J M (Nov 1998). "The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton". J. Biol. Chem. (UNITED STATES) 273 (45): 29745–29753. doi:10.1074/jbc.273.45.29745. ISSN 0021-9258. PMID 9792688. 
  16. ^ Rao, Radhakrishna K; Basuroy Shyamali, Rao Vijay U, Karnaky Jr Karl J, Gupta Akshay (Dec 2002). "Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress". Biochem. J. (England) 368 (Pt 2): 471–81. doi:10.1042/BJ20011804. ISSN 0264-6021. PMC 1222996. PMID 12169098. 

Further reading[edit]

External links[edit]