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Structural and functional characterization of CC chemokine CCL14.

Blain KY, Kwiatkowski W, Zhao Q, La Fleur D, Naik C, Chun TW, Tsareva T, Kanakaraj P, Laird MW, Shah R, George L, Sanyal I, Moore PA, Demeler B, Choe S
Biochemistry 46 10008-15 (2007)
Cited: 31 times
EuropePMC logo PMID: 17691823

Abstract

CC chemokine ligand 14, CCL14, is a human CC chemokine that is of recent interest because of its natural ability, upon proteolytic processing of the first eight NH2-terminal residues, to bind to and signal through the human immunodeficiency virus type-1 (HIV-1) co-receptor, CC chemokine receptor 5 (CCR5). We report X-ray crystallographic structures of both full-length CCL14 and signaling-active, truncated CCL14 [9-74] determined at 2.23 and 1.8 A, respectively. Although CCL14 and CCL14 [9-74] differ in their ability to bind CCR5 for biological signaling, we find that the NH2-terminal eight amino acids (residues 1 through 8) are completely disordered in CCL14 and both show the identical mode of the dimeric assembly characteristic of the CC type chemokine structures. However, analytical ultracentrifugation studies reveal that the CCL14 is stable as a dimer at a concentration as low as 100 nM, whereas CCL14 [9-74] is fully monomeric at the same concentration. By the same method, the equilibrium between monomers of CCL14 [9-74] and higher order oligomers is estimated to be of EC1,4 = 4.98 microM for monomer-tetramer conversion. The relative instability of CCL14 [9-74] oligomers as compared to CCL14 is also reflected in the Kd's that are estimated by the surface plasmon resonance method to be approximately 9.84 and 667 nM for CCL14 and CCL14 [9-74], respectively. This approximately 60-fold difference in stability at a physiologically relevant concentration can potentially account for their different signaling ability. Functional data from the activity assays by intracellular calcium flux and inhibition of CCR5-mediated HIV-1 entry show that only CCL14 [9-74] is fully active at these near-physiological concentrations where CCL14 [9-74] is monomeric and CCL14 is dimeric. These results together suggest that the ability of CCL14 [9-74] to monomerize can play a role for cellular activation.

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  2. How chemokines invite leukocytes to dance. Thelen M, Stein JV. Nat Immunol 9 953-959 (2008)
  3. Chemokine receptor CCR5: from AIDS to atherosclerosis. Jones KL, Maguire JJ, Davenport AP. Br J Pharmacol 162 1453-1469 (2011)
  4. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4. Korbecki J, Kojder K, Simińska D, Bohatyrewicz R, Gutowska I, Chlubek D, Baranowska-Bosiacka I. Int J Mol Sci 21 E8412 (2020)
  5. Survey of the year 2007 commercial optical biosensor literature. Rich RL, Myszka DG. J Mol Recognit 21 355-400 (2008)
  6. Chemokine receptor oligomerization and allostery. Stephens B, Handel TM. Prog Mol Biol Transl Sci 115 375-420 (2013)
  7. Chemokine oligomerization in cell signaling and migration. Wang X, Sharp JS, Handel TM, Prestegard JH. Prog Mol Biol Transl Sci 117 531-578 (2013)
  8. Neutralizing endogenous chemokines with small molecules. Principles and potential therapeutic applications. Galzi JL, Hachet-Haas M, Bonnet D, Daubeuf F, Lecat S, Hibert M, Haiech J, Frossard N. Pharmacol Ther 126 39-55 (2010)
  9. Dendritic cells as therapeutic targets in neuroinflammation. Luessi F, Zipp F, Witsch E. Cell Mol Life Sci 73 2425-2450 (2016)

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  2. A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia. Suply T, Hannedouche S, Carte N, Li J, Grosshans B, Schaefer M, Raad L, Beck V, Vidal S, Hiou-Feige A, Beluch N, Barbieri S, Wirsching J, Lageyre N, Hillger F, Debon C, Dawson J, Smith P, Lannoy V, Detheux M, Bitsch F, Falchetto R, Bouwmeester T, Porter J, Baumgarten B, Mansfield K, Carballido JM, Seuwen K, Bassilana F. Sci Signal 10 eaal0180 (2017)
  3. Recognition versus adaptive up-regulation and degradation of CC chemokines by the chemokine decoy receptor D6 are determined by their N-terminal sequence. Savino B, Borroni EM, Torres NM, Proost P, Struyf S, Mortier A, Mantovani A, Locati M, Bonecchi R. J Biol Chem 284 26207-26215 (2009)
  4. NMR analysis of the structure, dynamics, and unique oligomerization properties of the chemokine CCL27. Jansma AL, Kirkpatrick JP, Hsu AR, Handel TM, Nietlispach D. J Biol Chem 285 14424-14437 (2010)
  5. Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease. Li W, Liu L, Gomez A, Zhang J, Ramadan A, Zhang Q, Choi SW, Zhang P, Greenson JK, Liu C, Jiang D, Virts E, Kelich SL, Chu HW, Flynn R, Blazar BR, Hanenberg H, Hanash S, Paczesny S. JCI Insight 1 86660 (2016)
  6. Impaired Cell Cycle Regulation in a Natural Equine Model of Asthma. Pacholewska A, Jagannathan V, Drögemüller M, Klukowska-Rötzler J, Lanz S, Hamza E, Dermitzakis ET, Marti E, Leeb T, Gerber V. PLoS One 10 e0136103 (2015)
  7. CK12, a rainbow trout chemokine with lymphocyte chemo-attractant capacity associated to mucosal tissues. Montero J, Ordas MC, Alejo A, Gonzalez-Torres L, Sevilla N, Tafalla C. Mol Immunol 48 1102-1113 (2011)
  8. (Quasi-)racemic X-ray structures of glycosylated and non-glycosylated forms of the chemokine Ser-CCL1 prepared by total chemical synthesis. Okamoto R, Mandal K, Sawaya MR, Kajihara Y, Yeates TO, Kent SB. Angew Chem Int Ed Engl 53 5194-5198 (2014)
  9. CCL genes in multiple sclerosis and systemic lupus erythematosus. Vyshkina T, Sylvester A, Sadiq S, Bonilla E, Perl A, Kalman B. J Neuroimmunol 200 145-152 (2008)
  10. Pseudogenization of CCL14 in the Ochotonidae (pika) family. Neves F, Abrantes J, Lissovsky AA, Esteves PJ. Innate Immun 21 647-654 (2015)
  11. 3D profile-based approach to proteome-wide discovery of novel human chemokines. Tomczak A, Sontheimer J, Drechsel D, Hausdorf R, Gentzel M, Shevchenko A, Eichler S, Fahmy K, Buchholz F, Pisabarro MT. PLoS One 7 e36151 (2012)
  12. C-C motif chemokine 14 as a novel potential biomarker for predicting the prognosis of epithelial ovarian cancer. Cai Y, Ling Y, Huang L, Huang H, Chen X, Xiao Y, Zhu Z, Chen J. Oncol Lett 19 2875-2883 (2020)
  13. N-terminal Backbone Pairing Shifts in CCL5-12AAA14 Dimer Interface: Structural Significance of the FAY Sequence. Li JY, Chen YC, Lee YZ, Huang CH, Sue SC. Int J Mol Sci 21 1689 (2020)
  14. Endogenous Peptide Inhibitors of HIV Entry. Harms M, Hayn M, Zech F, Kirchhoff F, Münch J. Adv Exp Med Biol 1366 65-85 (2022)
  15. Performance of urinary C-C motif chemokine ligand 14 for the prediction of persistent acute kidney injury: a systematic review and meta-analysis. Chen YT, Pan HC, Hsu CK, Sun CY, Chen CY, Chen YH, Hsu HJ, Wu IW, Wu VC, Hoste E. Crit Care 27 318 (2023)
  16. Structure and Dynamics of Human Chemokine CCL16-Implications for Biological Activity. Weiergräber OH, Petrović D, Kislat A, Pattky M, Fabig J, Batra-Safferling R, Schulte Am Esch J, Hänel K, Huhn C, Strodel B, Homey B, Willbold D. Biomolecules 12 1588 (2022)


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