Uncoordinated-119 (Unc-119) Explained

Uncoordinated-119 (Unc-119) is a protein identified in a varieties of species including, C. elegans, humans, mice, zebrafish, rabbits, pig, calf, monkey, and protozoa.[1] This proteins have been classified in the GMP phosphodiesterase, delta superfamily.[2] Although Unc-119 proteins are categorized into their own family, they are shown to be ancestrally related to PrBP (prenyl binding protein) and rhoGDI. They are also known by several other names: Retinal Protein 4, HRG4, POC7 Centriolar Protein Homolog A, IMD13, POC7A, and RG4.  

Structure and function

In C. elegans, Unc-119 consistent of approximately 240 amino acids[3] with a mass of around ~26 kDa.[4] Using x-ray crystallography the protein's crystal structure was observed and found to have a resolution of 1.95 Å.[5] It has an immunoglobulin-like β-sandwich folding structure, resulting in a narrow, hydrophobic pocket.[6] This pocket can bind to lauroyl (C12) and myristoyl (C14) acyltransferase side chains, functioning as a transporter or lipid-binding chaperone. Unc-119 is crucial for the motility of cilium, maintaining their formation and function. This role is a conserved responsibility from animals to protozoa.

Role in cells

UNC-119 has been found to be involved in synaptic functions, signal transduction, endosome recycling, uptake of bacteria and endocytosis, protein trafficking, lipid-binding chaperone, and a mediator on Src family kinase signals.[7] [8]

The UNC-119 protein plays key roles in the movement and feeding in the C. elegans, because it is essential in the development and function of their nervous system. One mutation observed was in the expression patterns when the mutant fuses with lacZ.[6] When this protein is mutated or deleted, C. elegans were found to have problems moving, even to the point of complete paralysis. It was also proposed that a mutation could cause the C. elegans to lose the ability to recognize their food. When the organism possesses a mutated UNC-119, they have been shown to experience uncoordinated movement, a defect causing weak egg laying, and the inability to form dauer larvae.[8]

In H. sapiens, Unc-119 has been identified on chromosome 17 and is found predominantly in the retina (HRG4). It has been localized to the photo-receptor synapses in the outer plexiform layer of the retina, and suggested to play a role in the mechanism of photoreceptor neurotransmitter release through the synaptic vesicle cycle. Two transcript variants encoding different isoforms have been described for this gene. The encoded product shares strong homology with the C. elegans unc119 protein and it can functionally complement the C. elegans unc119 mutation.

Unc-119 has also been identified in other areas in humans, such as the liver, kidneys, brain, and fibroblasts.[6] It has also been found to play an important role within the T-cell receptor function[4] and interleukin-5 receptor (IL-5R) Unc-119 is an essential activator of both Lck and Fyn by interacting with their SH2- and SH3-binding domains. Mutation of the Unc-119 gene has been found to severely disrupt the T-cell receptor pathway. It has been suggested to be a cause of an immunodeficiency disorder known as idiopathic CD4 lymphopenia (ICL) due to the reduced t-cell stimulation.[5]

Interactions

Protein unc-119 homolog has been shown to interact with:

References

Further reading

Notes and References

  1. Swanson DA, Chang JT, Campochiaro PA, Zack DJ, Valle D . Mammalian orthologs of C. elegans unc-119 highly expressed in photoreceptors . Investigative Ophthalmology & Visual Science . 39 . 11 . 2085–94 . October 1998 . 9761287 .
  2. Fansa EK, Wittinghofer A . Sorting of lipidated cargo by the Arl2/Arl3 system . Small GTPases . 7 . 4 . 222–230 . October 2016 . 27806215 . 5129900 . 10.1080/21541248.2016.1224454 .
  3. Maduro M, Pilgrim D . Identification and cloning of unc-119, a gene expressed in the Caenorhabditis elegans nervous system . Genetics . 141 . 3 . 977–88 . November 1995 . 10.1093/genetics/141.3.977 . 8582641 . 1206859 .
  4. Gorska MM, Stafford SJ, Cen O, Sur S, Alam R . Unc119, a novel activator of Lck/Fyn, is essential for T cell activation . The Journal of Experimental Medicine . 199 . 3 . 369–79 . February 2004 . 14757743 . 2211793 . 10.1084/jem.20030589 .
  5. Constantine R, Zhang H, Gerstner CD, Frederick JM, Baehr W . Uncoordinated (UNC)119: coordinating the trafficking of myristoylated proteins . Vision Research . 75 . 26–32 . December 2012 . 23000199 . 3514684 . 10.1016/j.visres.2012.08.012 .
  6. Jean F, Pilgrim D . Coordinating the uncoordinated: UNC119 trafficking in cilia . European Journal of Cell Biology . 96 . 7 . 643–652 . October 2017 . 28935136 . 10.1016/j.ejcb.2017.09.001 .
  7. Lee Y, Chung S, Baek IK, Lee TH, Paik SY, Lee J . April 2013. UNC119a bridges the transmission of Fyn signals to Rab11, leading to the completion of cytokinesis . Cell Cycle . 12. 8. 1303–1315 . 10.4161/cc.24404 . 3674094. 23535298.
  8. Maduro MF, Gordon M, Jacobs R, Pilgrim DB . January 2000 . The UNC-119 family of neural proteins is functionally conserved between humans, Drosophila and C. elegans . Journal of Neurogenetics . 13. 4. 191–212 . 10858820. 10.3109/01677060009084494 . 36103225 .
  9. Kobayashi A, Kubota S, Mori N, McLaren MJ, Inana G . Photoreceptor synaptic protein HRG4 (UNC119) interacts with ARL2 via a putative conserved domain . FEBS Letters . 534 . 1–3 . 26–32 . January 2003 . 12527357 . 10.1016/S0014-5793(02)03766-3 . 22603052 . free .
  10. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE . A human protein-protein interaction network: a resource for annotating the proteome . Cell . 122 . 6 . 957–68 . September 2005 . 16169070 . 10.1016/j.cell.2005.08.029 . 11858/00-001M-0000-0010-8592-0 . 8235923 . free .
  11. Van Valkenburgh H, Shern JF, Sharer JD, Zhu X, Kahn RA . ADP-ribosylation factors (ARFs) and ARF-like 1 (ARL1) have both specific and shared effectors: characterizing ARL1-binding proteins . The Journal of Biological Chemistry . 276 . 25 . 22826–37 . June 2001 . 11303027 . 10.1074/jbc.M102359200 . free .
  12. Cen O, Gorska MM, Stafford SJ, Sur S, Alam R . Identification of UNC119 as a novel activator of SRC-type tyrosine kinases . The Journal of Biological Chemistry . 278 . 10 . 8837–45 . March 2003 . 12496276 . 10.1074/jbc.M208261200 . free .
  13. Alpadi K, Magupalli VG, Käppel S, Köblitz L, Schwarz K, Seigel GM, Sung CH, Schmitz F . RIBEYE recruits Munc119, a mammalian ortholog of the Caenorhabditis elegans protein unc119, to synaptic ribbons of photoreceptor synapses . The Journal of Biological Chemistry . 283 . 39 . 26461–7 . September 2008 . 18664567 . 3258921 . 10.1074/jbc.M801625200 . free .