Uncoordinated-119 (Unc-119) is a protein that has been identified in C. elegans, humans, mice, zebrafish, rabbits, pig, calf, monkey, and protozoa. [5] They have been classified in the GMP phosphodiesterase, delta superfamily. [6] Unc-119 proteins are categorized into their own family but are shown to be ancestrally related to PrBP (prenyl binding protein) and rhoGDI. It has been given many different names: Retinal Protein 4, HRG4, POC7 Centriolar Protein Homolog A, IMD13, POC7A, and RG4.
Unc-119 in C. elegans is approximately 240 amino acids [7] and has a mass of ~26 kDa. [8] Using x-ray crystallography the protein's crystal structure was observed and found to have a resolution of 1.95 Å. [9] It has an immunoglobulin-like β-sandwich folding structure, resulting in a narrow, hydrophobic pocket. [10] This pocket has ability to bind to lauroyl (C12) and myristoyl (C14) acyltransferase side chains as a transporter or lipid-binding chaperone. [9] Unc-119 helps with motility of cilium. It is needed for cilia to maintain formation and function. This is a conserved responsibility from animals to protozoa.
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. [11] [12]
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. [10] 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. [12]
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. [10] It has also been found to play an important role within the T-cell receptor function [8] 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. [9]
Protein unc-119 homolog has been shown to interact with:
ADP-ribosylation factor 6 (ARF6) is a member of the ADP ribosylation factor family of GTP-binding proteins. ARF6 has a variety of cellular functions that are frequently involved in trafficking of biological membranes and transmembrane protein cargo. ARF6 has specifically been implicated in endocytosis of plasma membrane proteins and also, to a lesser extent, plasma membrane protein recycling.
In molecular biology, CD4 is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984. In humans, the CD4 protein is encoded by the CD4 gene.
Lck is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T-cell receptor signaling in both naive T cells and effector T cells. The role of the Lck is less prominent in the activation or in the maintenance of memory CD8 T cells in comparison to CD4 T cells. In addition, the role of the lck varies among the memory T cells subsets. It seems that in mice, in the effector memory T cells (TEM) population, more than 50% of lck is present in a constitutively active conformation, whereas, only less than 20% of lck is present as active form of lck. These differences are due to differential regulation by SH2 domain–containing phosphatase-1 (Shp-1) and C-terminal Src kinase.
ADP ribosylation factors (ARFs) are members of the ARF family of GTP-binding proteins of the Ras superfamily. ARF family proteins are ubiquitous in eukaryotic cells, and six highly conserved members of the family have been identified in mammalian cells. Although ARFs are soluble, they generally associate with membranes because of N-terminus myristoylation. They function as regulators of vesicular traffic and actin remodelling.
Recoverin is a 23 kilodalton (kDa) neuronal calcium-binding protein that is primarily detected in the photoreceptor cells of the eye. It plays a key role in the inhibition of rhodopsin kinase, a molecule which regulates the phosphorylation of rhodopsin. A reduction in this inhibition helps regulate sensory adaptation in the retina, since the light-dependent channel closure in photoreceptors causes calcium levels to decrease, which relieves the inhibition of rhodopsin kinase by calcium-bound recoverin, leading to a more rapid inactivation of metarhodopsin II.
ZAP-70 is a protein normally expressed near the surface membrane of lymphocytes. It is most prominently known to be recruited upon antigen binding to the T cell receptor (TCR), and it plays a critical role in T cell signaling.
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.
Tyrosine-protein kinase Lyn is a protein that in humans is encoded by the LYN gene.
T-cell surface glycoprotein CD3 zeta chain also known as T-cell receptor T3 zeta chain or CD247 is a protein that in humans is encoded by the CD247 gene.
ARF GTPase-activating protein GIT1 is an enzyme that in humans is encoded by the GIT1 gene.
FYN binding protein (FYB-120/130), also known as FYB, ADAP, and SLAP-130 is a protein that is encoded by the FYB gene in humans. The protein is expressed in T cells, monocytes, mast cells, macrophages, NK cells, but not B cells. FYB is a multifunctional protein involved in post-activation T cell signaling, lymphocyte cytokine production, cell adhesion, and actin remodeling.
Regulating synaptic membrane exocytosis protein 1 is a protein that in humans is encoded by the RIMS1 gene.
Arrestin-C, also known as retinal cone arrestin-3, is a protein that in humans is encoded by the ARR3 gene.
Golgin subfamily A member 4 is a protein that in humans is encoded by the GOLGA4 gene.
ADP-ribosylation factor-like protein 3 is a protein that in humans is encoded by the ARL3 gene.
Protein unc-13 homolog B is a protein that in humans is encoded by the UNC13B gene.
ADP-ribosylation factor-like protein 1 is a protein that in humans is encoded by the ARL1 gene.
ADP-ribosylation factor-like protein 2 is a protein that in humans is encoded by the ARL2 gene.
Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta is an enzyme that in humans is encoded by the PDE6D gene. PDE6D was originally identified as a fourth subunit of rod cell-specific cGMP phosphodiesterase (PDE). The precise function of PDE delta subunit in the rod specific GMP-PDE complex is unclear. In addition, PDE delta subunit is not confined to photoreceptor cells but is widely distributed in different tissues. PDE delta subunit is thought to be a specific soluble transport factor for certain prenylated proteins and Arl2-GTP a regulator of PDE-mediated transport.
Rho GTPase-activating protein 32 is a protein that in humans is encoded by the RICS gene. RICS has two known isoforms, RICS that are expressed primarily at neurite growth cones, and at the post synaptic membranes, and PX-RICS which is more widely expressed in the endoplasmic reticulum, Golgi apparatus and endosomes. The only known domain of the RICS is the RhoGAP domain, whilst PX-RICS has an additional Phox homology and SH3 domain.
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