LU domain explained

The LU domain (Ly-6 antigen/uPAR) is an evolutionarily conserved protein domain of the three-finger protein superfamily. This domain is found in the extracellular domains of cell-surface receptors and in either GPI-anchored or secreted globular proteins, for example the Ly-6 family, CD59, and Sgp-2.[1] [2]

A variety of GPI-linked cell-surface glycoproteins are composed of one or more copies of a conserved LU domain of about 100 amino-acid residues.[3] [4] Among these proteins, most contain only a single LU domain, though small numbers of exceptions are known; well-studied family member uPAR has three tandem LU domains.

Structure

This domain folds into five antiparallel beta sheets, a structure common to the three-finger protein family. The domain typically contains ten well-conserved cysteine residues involved in five disulfide bonds, though some examples such as two of the three uPAR domains have fewer.

Examples

Besides uPAR, other receptors with LU domains include members of the transforming growth factor beta receptor (TGF-beta) superfamily, such as the activin type 2 receptor;[5] and bone morphogenetic protein receptor, type IA.[6] Other LU domain proteins are small globular proteins such as CD59 antigen, LYNX1, SLURP1, and SLURP2.[7]

Human proteins containing this domain

ARS; CD177; CD59; LY6D; LY6E; LY6H; LYNX1; LYPD2

LYPD3; LYPD4; LYPD5; LYPD6; PLAUR; PSCA; SLURP2
  • SLURP1; SPACA4; TEX101;

    • Functions

    Many LU domain containing proteins are involved in cholinergic signaling and bind acetylcholine receptors, notably linking their function to a common mechanism of 3FTx toxicity.[8] Members of the Ly6/uPAR family are believed to be the evolutionary ancestors of the three-finger toxin (3FTx).[9] Other LU proteins, such as the CD59 antigen, have well-studied functions in regulation of the immune system.

    Notes and References

    1. Kessler P, Marchot P, Silva M, Servent D . The three-finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions . Journal of Neurochemistry . 142 . 7–18 . August 2017 . Suppl 2 . 28326549 . 10.1111/jnc.13975 . free .
    2. Loughner CL, Bruford EA, McAndrews MS, Delp EE, Swamynathan S, Swamynathan SK . Organization, evolution and functions of the human and mouse Ly6/uPAR family genes . Human Genomics . 10 . 10 . April 2016 . 27098205 . 4839075 . 10.1186/s40246-016-0074-2 . free .
    3. Behrendt N, Ploug M, Patthy L, Houen G, Blasi F, Danø K . The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator . The Journal of Biological Chemistry . 266 . 12 . 7842–7 . April 1991 . 10.1016/S0021-9258(20)89526-X . 1850423 . free .
    4. Ploug M, Kjalke M, Rønne E, Weidle U, Høyer-Hansen G, Danø K . Localization of the disulfide bonds in the NH2-terminal domain of the cellular receptor for human urokinase-type plasminogen activator. A domain structure belonging to a novel superfamily of glycolipid-anchored membrane proteins . The Journal of Biological Chemistry . 268 . 23 . 17539–46 . August 1993 . 10.1016/S0021-9258(19)85366-8 . 8394346 . free .
    5. Greenwald J, Fischer WH, Vale WW, Choe S . Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase . Nature Structural Biology . 6 . 1 . 18–22 . January 1999 . 9886286 . 10.1038/4887 . 26301441 .
    6. Kirsch T, Sebald W, Dreyer MK . Crystal structure of the BMP-2-BRIA ectodomain complex . Nature Structural Biology . 7 . 6 . 492–6 . June 2000 . 10881198 . 10.1038/75903 . 19403233 .
    7. Galat A . The three-fingered protein domain of the human genome . Cellular and Molecular Life Sciences . 65 . 21 . 3481–93 . November 2008 . 18821057 . 10.1007/s00018-008-8473-8 . 19931506 . 11131612 .
    8. Tsetlin VI . Three-finger snake neurotoxins and Ly6 proteins targeting nicotinic acetylcholine receptors: pharmacological tools and endogenous modulators . Trends in Pharmacological Sciences . 36 . 2 . 109–23 . February 2015 . 25528970 . 10.1016/j.tips.2014.11.003 .
    9. Fry BG . From genome to "venome": molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins . Genome Research . 15 . 3 . 403–20 . March 2005 . 15741511 . 551567 . 10.1101/gr.3228405 .

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