XCL1

Chemokine (C motif) ligand (XCL1) is a small cytokine belonging to the C chemokine family that is also known as lymphotactin. Chemokines are known for their function in inflammatory and immunological responses. This family C chemokines differs in structure and function from most chemokines.[5][6] There are only two chemokines in this family and what separated them from other chemokines is that they only have two cysteines; one N-terminal cysteine and one cysteine downstream. These both are called Lymphotactin, alpha and beta form, and claim special characteristics only found between the two. Lymphotactins can go through a reversible conformational change which changes its binding shifts.[7]

XCL1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesXCL1, ATAC, LPTN, LTN, SCM-1, SCM-1a, SCM1, SCM1A, SCYC1, X-C motif chemokine ligand 1
External IDsOMIM: 600250 MGI: 104593 HomoloGene: 2250 GeneCards: XCL1
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1q24.2Start168,576,605 bp[1]
End168,582,069 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

6375

16963

Ensembl

ENSG00000143184

ENSMUSG00000026573

UniProt

P47992

P47993

RefSeq (mRNA)

NM_002995

NM_008510

RefSeq (protein)

NP_002986

NP_032536

Location (UCSC)Chr 1: 168.58 – 168.58 MbChr 1: 164.93 – 164.94 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

In normal tissues, XCL1 is found in high levels in spleen, thymus, small intestine and peripheral blood leukocytes, and at lower levels in lung, prostate gland and ovary. Secretion of XCL1 is responsible for the increase of intracellular calcium in peripheral blood lymphocytes.[8] Cellular sources for XCL1 include activated thymic and peripheral blood CD8+ T cells.[9][10][11] NK cells also secrete XCL1 along with other chemokines early in infections.[12] XCR1 expressing dendritic cells (DC) are a major target of XCL1.[12]

In humans, XCL1 is closely related to another chemokine called XCL2, whose gene is found at the same locus on chromosome 1.[11] Both of these chemokines share many genetic and functional similarities; however XCL2 has only been known to be observed in humans and not in mice.[12] XCL1 induces it chemotactic function by binding to a chemokine receptor called XCR1.[13] XCL1 is expressed on macrophages, fibroblasts, and specific lymphocytes.[6]

LTN, is found in two states: a monomer at 10 °C, LTN10, and a dimer at 40 °C, LTN40.[14]

Genomics

XCL1's gene is found on the long arm of chromosome 1, located on cytogenetic band q24.2 as seen in the infobox. The encoding gene is made of 6,017 DNA bases to encode for the protein XCL1.[15] This gene contains three exons and two introns as well as several transcription initiation sites.[8] This gene encodes for the 114-amino acid protein called XCL1 which is similar to other chemokines except that it lacks the first and third cysteine characteristics. This means that XCL1 only contains one cysteine creating a disulfide bond instead of two or three like the other chemokines.[5]

The genetic differences between XCL1 and XCL2 are very small. Both proteins are from the same family containing the C motif structure containing one disulfide bond and have almost identical tertiary structures.[8] These C chemokines also have the same flanking regions, meaning regions of the gene including the promoter and other places of protein binging that do not contribute to the RNA transcribed gene.[8] Gene mapping of this chemokine family shows similarities in their intron and exon locations with only one distinct difference. XCL1 has only one difference in its first intron that encodes for a large ribosomal subunit called L7a. In XCL2 have of the region encoding for L7a is cut off.[8] The only other genetic difference between the two mature proteins is the different amino acid in positions 7 and 8.[8][12] This amino acid difference may account for some biological differences. Some difficulties with comparing these two chemokines is that XCL2 has never been observed in a mouse.[12]

Structure

One thing that sets XCL1 apart from other cytokines is its structure.[7] While most chemokines have two disulfide bonds that connect the N-terminus to the core of the structure, XCL1 only has one.[5] This simple difference in disulfide bonds changes the overall tertiary structure of XCL1 from other chemokines. There are two parts of the lymphotactin protein, structures Ltn10 and Ltn40, that folds into each other, which make it biologically active.[7] This conformational change alters the binding structures on the chemokine. This understanding of the interfolding provides more of a basis to understanding to the lymphotactin kinetics.[7]

Biological Significance

Most of the secreted XCL1 comes from a specific kind of dendritic cell that is involved in antigen cross-presentation.[12] This means that XCL1 is involved in the activation of cytotoxic T cells by a dendritic cell. XCL1 can also be secreted by NK cells along with other chemokines in the beginning of infection. This has been associated with the T helper cell type 1 defense.[12] This secretion has also been observed to facilitate the NK cells to communicate with DC containing XCR1 on their surface. In the same way, secretion of XCL1 encourages Cytotoxic T cells to also communicate with DC containing SCR1.[12]

The pair of XCL1 and XCR1 are known to be involved in cross-presentation, antigen uptake, and induction of innate as well as adaptive cytotoxic immunity.[12]

XCL1 is also known to increate T cells in joints that are effected with rheumatoid arthritis.[6] They are also expressed on RA synovial lymphocytes.[6]

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References
  1. GRCh38: Ensembl release 89: ENSG00000143184 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000026573 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Wang X, Sharp JS, Handel TM, Prestegard JH (2013). "Chemokine oligomerization in cell signaling and migration". In Giraldo J, Ciruela F (eds.). Progress in Molecular Biology and Translational Science. 117. pp. 531–578. doi:10.1016/B978-0-12-386931-9.00020-9. ISBN 978-0-12-386931-9. PMC 3937849. PMID 23663982.
  6. Szekanecz Z, Koch AE (2017). "Cell Recruitment and Angiogenesis". In Firestein GS, Budd RC, Gabriel SE, McInnes IB, O'Dell JR (eds.). Kelly and Firestein's Textbook of Rheumatology. Elsevier. pp. 384–395. doi:10.1016/B978-0-323-31696-5.00025-5. ISBN 978-0-323-31696-5.
  7. Hundeiker M (2009). "[The clinical picture of the effects of radiation on the skin]". Strahlenschutz in Forschung Und Praxis. 28: 160–4. doi:10.1016/S0076-6879(09)05403-2. PMC 3686570. PMID 19480914.
  8. Yoshida T, Imai T, Takagi S, Nishimura M, Ishikawa I, Yaoi T, Yoshie O (October 14, 1996). "Structure and expression of two highly related genes encoding SCM-1/human lymphotactin". FEBS Letters. 395 (1): 82–88. doi:10.1016/0014-5793(96)01004-6. PMID 8849694.
  9. Kelner GS, Kennedy J, Bacon KB, Kleyensteuber S, Largaespada DA, Jenkins NA, Copeland NG, Bazan JF, Moore KW, Schall TJ (November 1994). "Lymphotactin: a cytokine that represents a new class of chemokine". Science. 266 (5189): 1395–9. doi:10.1126/science.7973732. PMID 7973732.
  10. Kennedy J, Kelner GS, Kleyensteuber S, Schall TJ, Weiss MC, Yssel H, Schneider PV, Cocks BG, Bacon KB, Zlotnik A (July 1995). "Molecular cloning and functional characterization of human lymphotactin". Journal of Immunology. 155 (1): 203–9. PMID 7602097.
  11. Yoshida T, Imai T, Takagi S, Nishimura M, Ishikawa I, Yaoi T, Yoshie O (October 1996). "Structure and expression of two highly related genes encoding SCM-1/human lymphotactin". FEBS Letters. 395 (1): 82–8. doi:10.1016/0014-5793(96)01004-6. PMID 8849694.
  12. Kroczek RA, Henn V (February 10, 2012). "The role of XCR1 and its Ligand XCL1 in antigen cross-presentation by murine and human dendritic cells". Front. Immunol. 3 (14). doi:10.3389/fimmu.2012.00014. PMC 3342032. PMID 22566900.
  13. Yoshida T, Imai T, Kakizaki M, Nishimura M, Takagi S, Yoshie O (June 1998). "Identification of single C motif-1/lymphotactin receptor XCR1". The Journal of Biological Chemistry. 273 (26): 16551–4. doi:10.1074/jbc.273.26.16551. PMID 9632725.
  14. Tyler RC, Murray NJ, Peterson FC, Volkman BF (August 2011). "Native-state interconversion of a metamorphic protein requires global unfolding". Biochemistry. 50 (33): 7077–9. doi:10.1021/bi200750k. PMC 3160782. PMID 21776971.
  15. "XCL1 Gene(Protein Coding)". GeneCards human gene database.
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