9GKG

Crystal structure of UNC119 in complex with Squarunkin A

Summary for 9GKG

• Entry DOI: 10.2210/pdb9gkg/pdb
• Descriptor: Protein unc-119 homolog A, squarunkin A, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 129584.85

Authors

Yelland, T.,Ismail, S. (deposition date: 2024-08-24, release date: 2025-01-15, Last modification date: 2026-01-28)

Primary citation

Samarakoon, Y.,Yelland, T.,Garcia-Gonzalez, E.,da Silva Justo Junior, A.,Mahmood, M.,Manoharan, A.,Patterson, S.,Serafin, V.,Gammage, P.A.,Marmiroli, S.,Halsey, C.,Ismail, S.,Roberts, E.W.
UNC119 regulates T-cell receptor signalling in primary T cells and T acute lymphocytic leukaemia.
Life Sci Alliance, 8:-, 2025

PubMed Abstract: T-cell receptor recognition of cognate peptide-MHC leads to the formation of signalling domains and the immunological synapse. Because of the close membrane apposition, there is rapid exclusion of CD45, and therefore LCK activation. Much less is known about whether spatial regulation of the intracellular face dictates LCK activity and TCR signal transduction. Moreover, as LCK is a driver in T acute lymphocytic leukaemia, it is important to understand its regulation. Here, we demonstrate a direct role of the ciliary protein UNC119 in trafficking LCK to the immunological synapse. Inhibiting UNC119 reduces localisation of LCK without impairing LCK phosphorylation and reduces T-cell receptor signal transduction. Although important for initial LCK reorganisation, activated CD8 T cells retained their ability to kill target tumour cells when UNC119 was inhibited. UNC119 was also needed to sustain proliferation in patient-derived T-ALL cells. UNC119 may therefore represent a novel therapeutic target in T acute lymphocytic leukaemia, which alters the subcellular localisation of LCK in T acute lymphocytic leukaemia cells but preserves the function of existing cytotoxic lymphocytes.

PubMed: 39814552
DOI: 10.26508/lsa.202403066

Experimental method

X-RAY DIFFRACTION (2.21 Å)