6h6a
From Proteopedia
Crystal structure of UNC119 in complex with LCK peptide
Structural highlights
Disease[U119A_HUMAN] Idiopathic CD4 lymphocytopenia;Cone rod dystrophy. Defects in UNC119 may be a cause of cone-rod dystrophy. A mutation was found in a 57-year-old woman with late-onset cone-rod dystrophy: from 40 year old, the patient suffered from poor night vision, defective color vision and light-sensitivity. At 57 year old, she displayed reduced visual acuity, myopa, macular atrophy and pericentral ring scotomas. The disease was caused by a heterozygous mutation causing premature termination and truncated UNC119 protein with dominant-negative effect. Function[U119A_HUMAN] Myristoyl-binding protein that acts as a cargo adapter: specifically binds the myristoyl moiety of a subset of N-terminally myristoylated proteins and is required for their localization. Binds myristoylated GNAT1 and is required for G-protein localization and trafficking in sensory neurons. Binds myristoylated NPHP3; however, in contrast to UNC119B, does not seem to play a major role in ciliary membrane localization of NPHP3. Does not bind all myristoylated proteins. Probably plays a role in trafficking proteins in photoreceptor cells.[1] [2] Publication Abstract from PubMedUpon engagement of the T cell receptor with an antigen-presenting cell, LCK initiates TCR signaling by phosphorylating its activation motifs. However, the mechanism of LCK activation specifically at the immune synapse is a major question. We show that phosphorylation of the LCK activating Y394, despite modestly increasing its catalytic rate, dramatically focuses LCK localization to the immune synapse. We describe a trafficking mechanism whereby UNC119A extracts membrane-bound LCK by sequestering the hydrophobic myristoyl group, followed by release at the target membrane under the control of the ciliary ARL3/ARL13B. The UNC119A N terminus acts as a "regulatory arm" by binding the LCK kinase domain, an interaction inhibited by LCK Y394 phosphorylation, thus together with the ARL3/ARL13B machinery ensuring immune synapse focusing of active LCK. We propose that the ciliary machinery has been repurposed by T cells to generate and maintain polarized segregation of signals such as activated LCK at the immune synapse. The Ciliary Machinery Is Repurposed for T Cell Immune Synapse Trafficking of LCK.,Stephen LA, ElMaghloob Y, McIlwraith MJ, Yelland T, Castro Sanchez P, Roda-Navarro P, Ismail S Dev Cell. 2018 Oct 8;47(1):122-132.e4. doi: 10.1016/j.devcel.2018.08.012. Epub, 2018 Sep 13. PMID:30220567[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | ElMaghloob, Y | Ismail, S | McIlwraith, M | Stephen, L | Yelland, T | Complex | Immune system | Kinase | Transport
