Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12.
Stem cell homing and breast cancer metastasis are orchestrated by the chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4. Here, we report the nuclear magnetic resonance structure of a constitutively dimeric SDF-1 in complex with a CXCR4 fragment that contains three sulfotyrosine residues important for a high-affinity ligand-receptor interaction. CXCR4 bridged the SDF-1 dimer interface so that sulfotyrosines sTyr7 and sTyr12 of CXCR4 occupied positively charged clefts on opposing chemokine subunits. Dimeric SDF-1 induced intracellular Ca2+ mobilization but had no chemotactic activity; instead, it prevented native SDF-1-induced chemotaxis, suggesting that it acted as a potent partial agonist. Our work elucidates the structural basis for sulfotyrosine recognition in the chemokine-receptor interaction and suggests a strategy for CXCR4-targeted drug development.
Veldkamp
Christopher T
CT
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Seibert
Christoph
C
Peterson
Francis C
FC
De la Cruz
Norberto B
NB
Haugner
John C
JC
Basnet
Harihar
H
Sakmar
Thomas P
TP
Volkman
Brian F
BF
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000737:chemistry* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; C005662:tyrosine O-sulfate; D014443:Tyrosine; D002118:Calcium
J Biol Chem. 2003 Jan 31;278(5):3378-85
12433920
Protein Sci. 1994 Dec;3(12):2254-71
7756983
JAMA. 2000 Jul 12;284(2):215-22
10889596
Biochemistry. 2005 Jul 12;44(27):9395-403
15996094
Trends Pharmacol Sci. 2007 Dec;28(12):615-20
18022255
J Mol Biol. 2006 Jun 23;359(5):1400-9
16725153
Science. 2007 Nov 23;318(5854):1258-65
17962520
EMBO J. 1997 Dec 1;16(23):6996-7007
9384579
J Biol Chem. 2007 Sep 21;282(38):27976-83
17644519
J Biol Chem. 1993 Apr 5;268(10):7283-9
8463264
Nature. 2001 Mar 1;410(6824):50-6
11242036
J Biol Chem. 1998 Aug 28;273(35):22279-83
9712844
Annu Rev Immunol. 1997;15:675-705
9143704
J Mol Biol. 2005 Jan 28;345(4):651-8
15588815
J Biol Chem. 2004 Aug 27;279(35):36175-8
15252057
Cytokine Growth Factor Rev. 2005 Dec;16(6):611-23
15979374
Nat Med. 1996 Dec;2(12):1293-300
8946819
Mol Pharmacol. 2005 Feb;67(2):460-9
15509716
J Immunol. 2006 Nov 15;177(10):6991-8
17082614
Curr Biol. 1998 Mar 26;8(7):369-76
9545196
Nat Med. 1998 Jan;4(1):72-7
9427609
Nat Methods. 2006 Dec;3(12):1001-6
17086179
Cell. 1999 Mar 5;96(5):667-76
10089882
Int J Cancer. 2006 Nov 1;119(9):2026-9
16671092
Cytometry A. 2003 Jan;51(1):35-45
12500303
Protein Sci. 2005 Apr;14(4):1071-81
15741341
J Leukoc Biol. 1994 Jun;55(6):763-70
8195702
Nature. 1998 Jun 11;393(6685):591-4
9634237
Science. 2007 Nov 23;318(5854):1266-73
17962519
Nature. 1998 Jun 11;393(6685):595-9
9634238
FASEB J. 1995 Jan;9(1):57-62
7821760
Protein Sci. 2006 Nov;15(11):2568-78
17075134
J Virol. 1999 Apr;73(4):2752-61
10074122
Methods Biochem Anal. 2003;44:89-113
12647383
Nature. 1996 Aug 15;382(6592):635-8
8757135
Science. 1996 May 10;272(5263):872-7
8629022
Nat Methods. 2007 Jan;4(1):3-4; author reply 4
17195017
Biochemistry. 1999 Feb 2;38(5):1402-14
9931005
J Biol Chem. 2002 Aug 16;277(33):29484-9
12034737
Protein Expr Purif. 2007 Mar;52(1):202-9
17071104
Biochemistry. 2006 Jun 27;45(25):7882-8
16784240
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1885-90
12571364
Cell. 2000 Oct 27;103(3):467-79
11081633
J Biol Chem. 2002 May 31;277(22):19418-23
11909868
J Mol Biol. 2006 Nov 3;363(4):813-22
16987528
Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11031-6
12169668
Nature. 1996 Aug 29;382(6594):829-33
8752280
J Biol Chem. 2002 Oct 25;277(43):40397-402
12183462
J Biol Chem. 2007 Mar 30;282(13):10018-10027
17264079
Am J Respir Cell Mol Biol. 2008 Jun;38(6):738-43
18218997
Protein Sci. 1997 Mar;6(3):609-17
9070443
J Interferon Cytokine Res. 2000 Aug;20(8):691-700
10954912
J Biol Chem. 1996 Apr 19;271(16):9579-86
8621632