The C-terminal peptide of CCL21 drastically augments CCL21 activity through the dendritic cell lymph node homing receptor CCR7 by interaction with the receptor N-terminus.

Publisher: Springer Country of Publication: Switzerland NLM ID: 9705402 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1420-9071 (Electronic) Linking ISSN: 1420682X NLM ISO Abbreviation: Cell Mol Life Sci Subsets: MEDLINE

Publication: Basel : Springer
Original Publication: Basel ; Boston : Birkhauser, c1997-

Chemokine CCL21/*metabolism ; Dendritic Cells/*metabolism ; Lymph Nodes/*metabolism ; Receptors, CCR7/*metabolism ; Receptors, Lymphocyte Homing/*metabolism ; Signal Transduction/*physiology; Animals ; CHO Cells ; Cells, Cultured ; Cricetulus ; Glycosylation ; Humans ; Ligands ; Peptides/metabolism ; Protein Binding/physiology ; Static Electricity

The endogenous chemokines CCL19 and CCL21 signal via their common receptor CCR7. CCL21 is the main lymph node homing chemokine, but a weak chemo-attractant compared to CCL19. Here we show that the 41-amino acid positively charged peptide, released through C-terminal cleavage of CCL21, C21TP, boosts the immune cell recruiting activity of CCL21 by up to 25-fold and the signaling activity via CCR7 by ~ 100-fold. Such boosting is unprecedented. Despite the presence of multiple basic glycosaminoglycan (GAG) binding motifs, C21TP boosting of CCL21 signaling does not involve interference with GAG mediated cell-surface retention. Instead, boosting is directly dependent on O-glycosylations in the CCR7 N-terminus. As dictated by the two-step binding model, the initial chemokine binding involves interaction of the chemokine fold with the receptor N-terminus, followed by insertion of the chemokine N-terminus deep into the receptor binding pocket. Our data suggest that apart from a role in initial chemokine binding, the receptor N-terminus also partakes in a gating mechanism, which could give rise to a reduced ligand activity, presumably through affecting the ligand positioning. Based on experiments that support a direct interaction of C21TP with the glycosylated CCR7 N-terminus, we propose that electrostatic interactions between the positively charged peptide and sialylated O-glycans in CCR7 N-terminus may create a more accessible version of the receptor and thus guide chemokine docking to generate a more favorable chemokine-receptor interaction, giving rise to the peptide boosting effect.
(© 2021. The Author(s).)

Trends Immunol. 2019 Jun;40(6):472-481. (PMID: 31006548)
Cell Mol Life Sci. 2009 Apr;66(8):1370-86. (PMID: 19099182)
Front Immunol. 2019 Sep 13;10:2156. (PMID: 31572374)
Front Immunol. 2016 Dec 09;7:568. (PMID: 28018341)
Biochem Biophys Res Commun. 2006 Sep 29;348(3):1089-93. (PMID: 16904643)
Biomed Microdevices. 2015 Apr;17(2):30. (PMID: 25681048)
ACS Chem Biol. 2007 Nov 20;2(11):735-44. (PMID: 18030990)
Eur J Immunol. 2001 Nov;31(11):3291-7. (PMID: 11745346)
J Immunol. 2014 Apr 15;192(8):3908-3914. (PMID: 24639348)
Int J Mol Sci. 2017 Aug 25;18(9):. (PMID: 28841151)
J Exp Med. 1998 Jul 20;188(2):373-86. (PMID: 9670049)
Curr Opin Struct Biol. 2020 Jun;62:102-111. (PMID: 31927217)
J Chem Inf Model. 2016 Sep 26;56(9):1808-22. (PMID: 27529431)
NMR Biomed. 2012 Sep;25(9):1095-103. (PMID: 22315137)
J Biol Chem. 2004 May 28;279(22):23214-22. (PMID: 15054093)
Front Immunol. 2014 Jun 23;5:277. (PMID: 25002861)
J Mol Graph Model. 2017 Jun;74:352-358. (PMID: 28477575)
Mol Syst Biol. 2018 Nov 20;14(11):e8486. (PMID: 30459171)
J Leukoc Biol. 2016 Jun;99(6):869-82. (PMID: 26729814)
Nat Methods. 2018 Nov;15(11):881-888. (PMID: 30104636)
Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):. (PMID: 33875601)
J Exp Med. 2011 Sep 26;208(10):2141-53. (PMID: 21930767)
J Biol Chem. 2007 Apr 6;282(14):10576-84. (PMID: 17283075)
Cell Rep. 2016 Feb 23;14(7):1723-1734. (PMID: 26876174)
Immunol Cell Biol. 2016 Nov;94(10):955-963. (PMID: 27301418)
ACS Pharmacol Transl Sci. 2020 Mar 17;3(2):237-245. (PMID: 32296765)
Science. 2016 Jan 8;351(6269):186-90. (PMID: 26657283)
Annu Rev Pharmacol Toxicol. 2006;46:481-519. (PMID: 16402913)
J Leukoc Biol. 2018 Aug;104(2):401-411. (PMID: 29768676)
J Biol Chem. 2004 Oct 8;279(41):42383-92. (PMID: 15284247)
Cancer Cell. 2018 Apr 9;33(4):563-569. (PMID: 29634944)
Sci Rep. 2017 Aug 17;7(1):8536. (PMID: 28819198)
J Biol Chem. 1998 Mar 20;273(12):7118-22. (PMID: 9507024)
J Exp Med. 2001 Dec 3;194(11):1661-73. (PMID: 11733580)
J Leukoc Biol. 2018 Aug;104(2):375-389. (PMID: 29603364)
Cell. 2015 May 21;161(5):1101-1111. (PMID: 25981665)
Immunity. 2010 May 28;32(5):703-13. (PMID: 20471289)
Mol Cell. 2019 Jul 25;75(2):394-407.e5. (PMID: 31227230)
Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5614-9. (PMID: 21422278)
Nat Chem Biol. 2006 Sep;2(9):467-73. (PMID: 16878128)
Nat Commun. 2020 Aug 10;11(1):3990. (PMID: 32778659)
EMBO J. 2013 May 15;32(10):1478-88. (PMID: 23584533)
J Biol Chem. 1987 Sep 5;262(25):12189-95. (PMID: 2957376)
Clin Immunol. 2001 Apr;99(1):43-52. (PMID: 11286540)
Cytotherapy. 2016 Sep;18(9):1187-96. (PMID: 27424146)
J Leukoc Biol. 2016 Jun;99(6):993-1007. (PMID: 26819318)
Biochemistry. 2020 Apr 7;59(13):1338-1350. (PMID: 32182428)
Cell. 2019 Aug 22;178(5):1222-1230.e10. (PMID: 31442409)

F30 CA210587 United States CA NCI NIH HHS; R01 GM097381 United States GM NIGMS NIH HHS; 0057954 Novo Nordisk Fonden (DK); DNRF107 Statens Naturvidenskabelige Forskningsrad

Keywords: CCR7; Chemokine; Dendritic cell; Glycosylation; Peptide

0 (CCL21 protein, human)
0 (CCR7 protein, human)
0 (Chemokine CCL21)
0 (Ligands)
0 (Peptides)
0 (Receptors, CCR7)
0 (Receptors, Lymphocyte Homing)
0 (polypeptide C)

Date Created: 20210929 Date Completed: 20211108 Latest Revision: 20220716

20240829

PMC8558179

10.1007/s00018-021-03930-7

34586443