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The '''LU domain''' ([[LY6|Ly-6 antigen]]/[[urokinase plasminogen activator receptor|uPAR]]) is an evolutionally conserved protein domain of the [[three finger protein]] superfamily. This domain is found in the [[extracellular domain]]s of [[cell-surface receptor]]s and in either [[GPI-anchor]]ed or [[secreted]] [[globular protein]]s, for example the Ly-6 family, [[CD59]], thymocyte B cell antigen (LY6), and Sgp-2.<ref name=kessler_2017>{{Cite journal|last=Kessler|first=Pascal|last2=Marchot|first2=Pascale|last3=Silva|first3=Marcela|last4=Servent|first4=Denis|date=2017-03-01|title=The three-finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions|journal=Journal of Neurochemistry|volume=142|language=en|pages=7–18|doi=10.1111/jnc.13975|pmid=28326549|issn=1471-4159}}</ref>
The '''LU domain''' ([[LY6|Ly-6 antigen]]/[[urokinase plasminogen activator receptor|uPAR]]) is an evolutionally conserved protein domain of the [[three-finger protein]] superfamily. This domain is found in the [[extracellular domain]]s of [[cell-surface receptor]]s and in either [[GPI-anchor]]ed or [[secreted]] [[globular protein]]s, for example the Ly-6 family, [[CD59]], and Sgp-2.<ref name=kessler_2017>{{Cite journal|last=Kessler|first=Pascal|last2=Marchot|first2=Pascale|last3=Silva|first3=Marcela|last4=Servent|first4=Denis|date=2017-03-01|title=The three-finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions|journal=Journal of Neurochemistry|volume=142|language=en|pages=7–18|doi=10.1111/jnc.13975|pmid=28326549|issn=1471-4159}}</ref><ref name=loughner_2016>{{Cite journal|last=Loughner|first=Chelsea L.|last2=Bruford|first2=Elspeth A.|last3=McAndrews|first3=Monica S.|last4=Delp|first4=Emili E.|last5=Swamynathan|first5=Sudha|last6=Swamynathan|first6=Shivalingappa K.|date=2016-01-01|title=Organization, evolution and functions of the human and mouse Ly6/uPAR family genes|journal=Human Genomics|volume=10|pages=10|doi=10.1186/s40246-016-0074-2|issn=1479-7364|pmc=4839075|pmid=27098205}}</ref>


A variety of GPI-linked cell-surface glycoproteins are composed of one or more copies of a conserved domain of about 100 amino-acid residues.<ref name="PUB00002692">{{cite journal |vauthors=Patthy L, Blasi F, Behrendt N, Ploug M, Houen G, Dano K |title=The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator |journal=J. Biol. Chem. |volume=266 |issue=12 |pages=7842–7847 |year=1991 |pmid=1850423}}</ref><ref name="PUB00002796">{{cite journal |vauthors=Ploug M, Dano K, Kjalke M, Ronne E, Weidle U, Hoyer-Hansen G |title=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 |journal=J. Biol. Chem. |volume=268 |issue=23 |pages=17539–17546 |year=1993 |pmid=8394346}}</ref> Among these proteins, U-PAR contains three tandem copies of the domain, while all the others are made up of a single domain.
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.<ref name="PUB00002692">{{cite journal |vauthors=Patthy L, Blasi F, Behrendt N, Ploug M, Houen G, Dano K |title=The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator |journal=J. Biol. Chem. |volume=266 |issue=12 |pages=7842–7847 |year=1991 |pmid=1850423}}</ref><ref name="PUB00002796">{{cite journal |vauthors=Ploug M, Dano K, Kjalke M, Ronne E, Weidle U, Hoyer-Hansen G |title=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 |journal=J. Biol. Chem. |volume=268 |issue=23 |pages=17539–17546 |year=1993 |pmid=8394346}}</ref> 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]];<ref name=greenwald_1999>{{Cite journal|last=Greenwald|first=Jason|last2=Fischer|first2=Wolfgang H.|last3=Vale|first3=Wylie W.|last4=Choe|first4=Senyon|title=Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase|journal=Nature Structural Biology|language=en|volume=6|issue=1|pages=18–22|doi=10.1038/4887|pmid=9886286|year=1999}}</ref> and [[bone morphogenetic protein receptor, type IA]].<ref>{{Cite journal|last=Kirsch|first=Thomas|last2=Sebald|first2=Walter|last3=Dreyer|first3=Matthias K.|title=Crystal structure of the BMP-2−BRIA ectodomain complex|journal=Nature Structural Biology|language=en|volume=7|issue=6|pages=492–496|doi=10.1038/75903|pmid=10881198|year=2000}}</ref> Other LU domain proteins are small globular proteins such as [[CD59 antigen]], [[LYNX1]], [[SLURP1]], and [[SLURP2]].<ref name=kessler_2017 /><ref name=galat_2008>{{Cite journal|last=Galat|first=A.|date=2008-11-01|title=The three-fingered protein domain of the human genome|journal=Cellular and Molecular Life Sciences|language=en|volume=65|issue=21|pages=3481–3493|doi=10.1007/s00018-008-8473-8|pmid=18821057|issn=1420-682X}}</ref>

Many LU domain containing proteins are involved in [[cholinergic]] signaling and bind [[acetylcholine]] receptors, notably linking their function to a common [[mechanism of action|mechanism]] of 3FTx toxicity.<ref name=kessler_2017 /><ref name=loughner_2016 /><ref name=tsetlin_2015>{{Cite journal|last=Tsetlin|first=Victor I.|date=2015-02-01|title=Three-finger snake neurotoxins and Ly6 proteins targeting nicotinic acetylcholine receptors: pharmacological tools and endogenous modulators|journal=Trends in Pharmacological Sciences|volume=36|issue=2|pages=109–123|doi=10.1016/j.tips.2014.11.003|issn=1873-3735|pmid=25528970}}</ref> Members of the Ly6/uPAR family are believed to be the evolutionary ancestors of 3FTx toxins.<ref name=fry_2005>{{Cite journal|last=Fry|first=Bryan G.|date=2005-03-01|title=From genome to "venome": Molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins|journal=Genome Research|language=en|volume=15|issue=3|pages=403–420|doi=10.1101/gr.3228405|issn=1088-9051|pmc=551567|pmid=15741511}}</ref> Other LU proteins, such as the [[CD59 antigen]], have well-studied functions in regulation of the [[immune system]].<ref name=tsetlin_2015 />


== Structure ==

This domain folds into three antiparallel beta sheets, a common


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

Revision as of 01:44, 1 June 2019

u-PAR/Ly-6 domain
Crystallographic structure of non-glycosylated human CD59.[1]
Identifiers
SymbolUPAR_LY6
PfamPF00021
InterProIPR001526
PROSITEPDOC00756
SCOP21erg / SCOPe / SUPFAM
CDDcd00117
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1cds :28-95 1cdr :28-95 1cdq :28-95 1erg :28-95 1ywhC:25-99 1vyeA:23-80

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]

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 3FTx toxins.[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 three antiparallel beta sheets, a common

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;

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. 63 (Pt 8): 648–52. doi:10.1107/S1744309107033477. PMC 2335151. PMID 17671359.
  2. ^ a b c Kessler, Pascal; Marchot, Pascale; Silva, Marcela; Servent, Denis (2017-03-01). "The three-finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions". Journal of Neurochemistry. 142: 7–18. doi:10.1111/jnc.13975. ISSN 1471-4159. PMID 28326549.
  3. ^ a b Loughner, Chelsea L.; Bruford, Elspeth A.; McAndrews, Monica S.; Delp, Emili E.; Swamynathan, Sudha; Swamynathan, Shivalingappa K. (2016-01-01). "Organization, evolution and functions of the human and mouse Ly6/uPAR family genes". Human Genomics. 10: 10. doi:10.1186/s40246-016-0074-2. ISSN 1479-7364. PMC 4839075. PMID 27098205.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ Patthy L, Blasi F, Behrendt N, Ploug M, Houen G, Dano K (1991). "The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator". J. Biol. Chem. 266 (12): 7842–7847. PMID 1850423.
  5. ^ Ploug M, Dano K, Kjalke M, Ronne E, Weidle U, Hoyer-Hansen G (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". J. Biol. Chem. 268 (23): 17539–17546. PMID 8394346.
  6. ^ Greenwald, Jason; Fischer, Wolfgang H.; Vale, Wylie W.; Choe, Senyon (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, Thomas; Sebald, Walter; Dreyer, Matthias K. (2000). "Crystal structure of the BMP-2−BRIA ectodomain complex". Nature Structural Biology. 7 (6): 492–496. doi:10.1038/75903. PMID 10881198.
  8. ^ Galat, A. (2008-11-01). "The three-fingered protein domain of the human genome". Cellular and Molecular Life Sciences. 65 (21): 3481–3493. doi:10.1007/s00018-008-8473-8. ISSN 1420-682X. PMID 18821057.
  9. ^ a b Tsetlin, Victor I. (2015-02-01). "Three-finger snake neurotoxins and Ly6 proteins targeting nicotinic acetylcholine receptors: pharmacological tools and endogenous modulators". Trends in Pharmacological Sciences. 36 (2): 109–123. doi:10.1016/j.tips.2014.11.003. ISSN 1873-3735. PMID 25528970.
  10. ^ Fry, Bryan G. (2005-03-01). "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): 403–420. doi:10.1101/gr.3228405. ISSN 1088-9051. PMC 551567. PMID 15741511.
This article incorporates text from the public domain Pfam and InterPro: IPR001526
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