LU domain

The LU domain (Ly-6 antigen/uPAR) is an evolutionally 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.[2][3]

u-PAR/Ly-6 domain
Identifiers
SymbolUPAR_LY6
PfamPF00021
InterProIPR001526
PROSITEPDOC00756
CATH1erg
SCOPe1erg / SUPFAM
CDDcd00117

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.[4][5] Among these proteins, U-PAR contains three tandem copies of the domain, while all the others are made up of a single domain.

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;[6] and bone morphogenetic protein receptor, type IA.[7] Other LU domain proteins are small globular proteins such as CD59 antigen, LYNX1, SLURP1, and SLURP2.[2][8]

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.[2][3][9] Members of the Ly6/uPAR family are believed to be the evolutionary ancestors of the three-finger toxin (3FTx).[10] Other LU proteins, such as the CD59 antigen, have well-studied functions in regulation of the immune system.[9]

Structure

This domain folds into five antiparallel beta sheets, a structure common to the three-finger superfamily.

As shown in the following schematic, this conserved domain contains 10 cysteine residues involved in five disulfide bonds - in U-PAR, the first copy of the domain lacks the fourth disulfide bond.

    +------+     +------------------------+                    +---+
    |      |     |                        |                    |   |
xCxxCxxxxxxCxxxxxCxxxxxCxxxxxxxxxxxxxxxxxxCxxxxCxxxxxxxxxxxxxxCCxxxCxxxxxxxx
 |                     |                       |              |
 +---------------------+                       +--------------+

'C': conserved cysteine involved in a disulfide bond.

Subfamilies

Human proteins containing this domain

ARS; CD177; CD59; LY6D; LY6E; LY6H; LYNX1; LYPD2; LYPD3; LYPD4; LYPD5; LYPD6; PLAUR; PSCA; SLURP2; SLURP1; SPACA4; TEX101;

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References
  1. PDB: 2J8B​; Leath KJ, Johnson S, Roversi P, Hughes TR, Smith RA, Mackenzie L, Morgan BP, Lea SM (August 2007). "High-resolution structures of bacterially expressed soluble human CD59". Acta Crystallographica. Section F, Structural Biology and Crystallization Communications. 63 (Pt 8): 648–52. doi:10.1107/S1744309107033477. PMC 2335151. PMID 17671359.
  2. Kessler P, Marchot P, Silva M, Servent D (August 2017). "The three-finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions". Journal of Neurochemistry. 142 Suppl 2: 7–18. doi:10.1111/jnc.13975. PMID 28326549.
  3. Loughner CL, Bruford EA, McAndrews MS, Delp EE, Swamynathan S, Swamynathan SK (April 2016). "Organization, evolution and functions of the human and mouse Ly6/uPAR family genes". Human Genomics. 10: 10. doi:10.1186/s40246-016-0074-2. PMC 4839075. PMID 27098205.
  4. Behrendt N, Ploug M, Patthy L, Houen G, Blasi F, Danø K (April 1991). "The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator". The Journal of Biological Chemistry. 266 (12): 7842–7. PMID 1850423.
  5. Ploug M, Kjalke M, Rønne E, Weidle U, Høyer-Hansen G, Danø K (August 1993). "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. PMID 8394346.
  6. Greenwald J, Fischer WH, Vale WW, Choe S (January 1999). "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. doi:10.1038/4887. PMID 9886286.
  7. Kirsch T, Sebald W, Dreyer MK (June 2000). "Crystal structure of the BMP-2-BRIA ectodomain complex". Nature Structural Biology. 7 (6): 492–6. doi:10.1038/75903. PMID 10881198.
  8. Galat A (November 2008). "The three-fingered protein domain of the human genome". Cellular and Molecular Life Sciences. 65 (21): 3481–93. doi:10.1007/s00018-008-8473-8. PMID 18821057.
  9. Tsetlin VI (February 2015). "Three-finger snake neurotoxins and Ly6 proteins targeting nicotinic acetylcholine receptors: pharmacological tools and endogenous modulators". Trends in Pharmacological Sciences. 36 (2): 109–23. doi:10.1016/j.tips.2014.11.003. PMID 25528970.
  10. Fry BG (March 2005). "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. doi:10.1101/gr.3228405. PMC 551567. PMID 15741511.
This article incorporates text from the public domain Pfam and InterPro: IPR001526
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