title: Structural insight into the evolution of a new chemokine family from zebrafish.
abstract: The mammalian chemokine family is segregated into four families - CC, CXC, CX3C, and XC-based on the arrangement of cysteines and the corresponding disulfides. Sequencing of the Danio rerio (zebrafish) genome has identified more than double the amount of human chemokines with the absence of the CX3C family and the presence of a new family, CX. The only other family with a single cysteine in the N-terminal region is the XC family. Human lymphotactin (XCL1) has two interconverting structures due to dynamic changes that occur in the protein. Similar to an experiment with XCL1 that identified the two structural forms, we probed for multiple forms of zCXL1 using heparin affinity. The results suggest only a single form of CXL1 is present. We used sulfur-SAD phasing to determine the three-dimensional structure CXL1. Zebrafish CXL1 (zCXL1) has three disulfides that appear to be important for a stable structure. One disulfide is common to all chemokines except those that belong to the XC family, another is similar to a subset of CC chemokines containing three disulfides, but the third disulfide is unique to the CX family. We analyzed the electrostatic potential of the zCXL1 structure and identified the likely heparin-binding site for glycosaminoglycans (GAGs). zCXL1 has a similar sequence identity with human CCL5 and CXCL12, but the structure is more related to CCL5. Our structural analysis supports the phylogenetic and genomic studies on the evolution of the CXL family.
authors.affiliation: Department of Pharmacology, Yale University, New Haven, Connecticut, 06520-8066.
authors.forename: Deepa
authors.initials: D
authors.lastname: Rajasekaran
authors.forename: Chengpeng
authors.initials: C
authors.lastname: Fan
authors.forename: Wuyi
authors.initials: W
authors.lastname: Meng
authors.forename: James W
authors.initials: JW
authors.lastname: Pflugrath
authors.forename: Elias J
authors.initials: EJ
authors.lastname: Lolis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018925:Chemokines / Q000737:chemistry* / Q000235:genetics*; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000378:metabolism; D019143:Evolution, Molecular; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D040681:Structural Homology, Protein; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000235:genetics*
chemical_list: D018925:Chemokines; D004220:Disulfides; D029961:Zebrafish Proteins; D006493:Heparin
keywords: CX chemokine family; Danio rerio (zebrafish) chr24a2/CXL34bk3 (CXL1); Sulfur SAD; chemokine structure; heparin binding
references.citation: Acta Crystallogr D Biol Crystallogr. 2003 Nov;59(Pt 11):1943-57
references.pmid: 14573949
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
references.pmid: 21460441
references.citation: Structure. 2011 Aug 10;19(8):1138-48
references.pmid: 21827949
references.citation: Acta Crystallogr D Biol Crystallogr. 2008 Jan;64(Pt 1):61-9
references.pmid: 18094468
references.citation: Genes Cells. 2013 Jan;18(1):1-16
references.pmid: 23145839
references.citation: Biochemistry. 2012 Jul 17;51(28):5642-54
references.pmid: 22686371
references.citation: Biochemistry. 2007 Mar 13;46(10):2564-73
references.pmid: 17302442
references.citation: Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):502-6
references.pmid: 1988949
references.citation: Proteins. 2010 Apr;78(5):1331-7
references.pmid: 20077567
references.citation: J Interferon Cytokine Res. 2000 Aug;20(8):691-700
references.pmid: 10954912
references.citation: Acta Crystallogr D Biol Crystallogr. 2009 Jun;65(Pt 6):582-601
references.pmid: 19465773
references.citation: Annu Rev Biochem. 2005;74:385-410
references.pmid: 15952892
references.citation: Proteins. 2007 Jun 1;67(4):1193-7
references.pmid: 17357154
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5057-62
references.pmid: 18364395
references.citation: Biochemistry. 2011 Aug 23;50(33):7077-9
references.pmid: 21776971
references.citation: Protein Sci. 2009 Jul;18(7):1359-69
references.pmid: 19551879
references.citation: Science. 2012 May 25;336(6084):1033-7
references.pmid: 22628655
references.citation: J Mol Biol. 2007 Sep 21;372(3):774-97
references.pmid: 17681537
references.citation: EMBO J. 1997 Dec 1;16(23):6996-7007
references.pmid: 9384579
references.citation: BMC Genomics. 2008 May 15;9:222
references.pmid: 18482437
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6941-6
references.pmid: 9618518
references.citation: J Biol Chem. 2004 Mar 26;279(13):12598-604
references.pmid: 14707146
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
references.pmid: 20383002
references.citation: Immunity. 2012 May 25;36(5):705-16
references.pmid: 22633458
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
references.pmid: 20124692
references.citation: Biochemistry. 1999 Jun 15;38(24):7653-8
references.pmid: 10387004
references.citation: Annu Rev Pharmacol Toxicol. 2002;42:469-99
references.pmid: 11807180
references.citation: J Biol Chem. 2007 Mar 30;282(13):10018-10027
references.pmid: 17264079