NMR Studies of Active N-terminal Peptides of Stromal Cell-derived Factor-1 (2000)

Stromal cell-derived factor 1 (SDF-1), a member of the CXC chemokine family, is the only chemokine to bind to the receptor CXCR4. This receptor is also a co-receptor for syncytia-inducing forms of HIV in CD4+ cells. In addition, SDF-1 is responsible for attracting mature lymphocytes to the bone marrow and can therefore contribute to host versusgraft rejection in bone marrow transplantation. Clearly, by manipulating SDF-1 activity, we could find a possible anti-viral AIDS treatment and aid in bone marrow transplantation. SDF-1 binds to CXCR4 primarily via the N terminus, which appears flexible in the recently determined three-dimensional structure of SDF-1. Strikingly, short N-terminal SDF-1 peptides have been shown to have significant SDF-1 activity. By using NMR, we have determined the major conformation of the N terminus of SDF-1 in a 17-mer (residues 1–17 of SDF-1) and a 9-mer dimer (residues 1–9 of SDF-1 linked by a disulfide bond at residue 9). Residues 5–8 and 11–14 form similar structures that can be characterized as a β-turn of the β-αR type. These structural motifs are likely to be interconverting with other states, but the major conformation may be important for recognition in receptor binding. These results suggest for the first time that there may be a link between structuring of short N-terminal chemokine peptides and their ability to activate their receptor. These studies will act as a starting point for synthesizing non-peptide analogs that act as CXCR4 antagonists. Stromal cell-derived factor 1 (SDF-1), a member of the CXC chemokine family, is the only chemokine to bind to the receptor CXCR4. This receptor is also a co-receptor for syncytia-inducing forms of HIV in CD4+ cells. In addition, SDF-1 is responsible for attracting mature lymphocytes to the bone marrow and can therefore contribute to host versusgraft rejection in bone marrow transplantation. Clearly, by manipulating SDF-1 activity, we could find a possible anti-viral AIDS treatment and aid in bone marrow transplantation. SDF-1 binds to CXCR4 primarily via the N terminus, which appears flexible in the recently determined three-dimensional structure of SDF-1. Strikingly, short N-terminal SDF-1 peptides have been shown to have significant SDF-1 activity. By using NMR, we have determined the major conformation of the N terminus of SDF-1 in a 17-mer (residues 1–17 of SDF-1) and a 9-mer dimer (residues 1–9 of SDF-1 linked by a disulfide bond at residue 9). Residues 5–8 and 11–14 form similar structures that can be characterized as a β-turn of the β-αR type. These structural motifs are likely to be interconverting with other states, but the major conformation may be important for recognition in receptor binding. These results suggest for the first time that there may be a link between structuring of short N-terminal chemokine peptides and their ability to activate their receptor. These studies will act as a starting point for synthesizing non-peptide analogs that act as CXCR4 antagonists. human immunodeficiency virus stromal cell derived factor 1 Nuclear Overhauser enhancement NOE spectroscopy rotating frame effect Overhauser enhancement parts per thousand high pressure liquid chromatography chemical shift deviation total correlation spectroscopy Chemokines are an important class of proteins in the immune system that act to recruit leukocytes to sites of inflammation and infection by interacting with specific receptors on the cell surface of their target cells (for reviews see Refs. 1Horuk R. Trends Pharmacol. Sci. 1994; 15: 159-165Abstract Full Text PDF PubMed Scopus (157) Google Scholar and 2Miller M.D. Krangel M.S. Crit. Rev. Immunol. 1992; 12: 17-46PubMed Google Scholar). 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Sullivan N. Rollins B. Ponath P.D. Wu L. Mackay C.R. LaRosa G. Newman W. Gerard N. Gerard C. Sodroski J. Cell. 1996; 85: 1135-1148Abstract Full Text Full Text PDF PubMed Scopus (2091) Google Scholar). Human chemokines are approximately 70–80 residues in length and share substantial sequence and structural similarity (14Clark-Lewis I. Kim K. Rajarathnam K. Gong J. Dewald B. Moser B. Baggiolini M. Sykes B.D. J. Leukocyte Biol. 1995; 57: 703-711Crossref PubMed Scopus (336) Google Scholar). There are two major classes of chemokines, the CC chemokines (RANTES, MCP-1, MIP-1α, and MIP-1β) and the CXC chemokines (IL-8, NAP-2, MGSA, and SDF-1), so named because of the spacing between the cysteine residues near the N terminus of these proteins. Stromal cell-derived factor-1 (SDF-1) is a member of the CXC chemokine family and is expressed constitutively in a broad range of tissues. SDF-1 has a fundamental role in trafficking, export, and homing of bone marrow cells (15Loetscher P. Gong J. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1998; 273: 22279-22283Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Tissue distribution of SDF-1 suggests that it may have a role in immune surveillance rather than inflammation (16Bleul C.C. Fuhlbrigge R.C. Casasnovas J.M. Aiuti A. Springer T.A. J. Exp. Med. 1996; 184: 1101-1109Crossref PubMed Scopus (1284) Google Scholar). SDF-1 has exceptionally strong sequence conservation between species (17Shirouzu M. Nakano T. Inazawa J. Tashiro K. Tada H. Shinohara T. Honjo T. Genomics. 1995; 28: 495-500Crossref PubMed Scopus (536) Google Scholar) and is the only known natural ligand for the CXC chemokine receptor 4 (CXCR4) (8Oberlin E. Amara A. Bachelerie F. Bessia C. Virelizier J. Arenzana-Seisdedos F. Schwartz O. Heard J. Clark-Lewis I. Legler D.F. Loetscher M. Baggiolini M. Moser B. Nature. 1996; 382: 833-835Crossref PubMed Scopus (1482) Google Scholar). The recently solved structure of SDF-1 (18Crump M.P. Gong J. Loetscher P. Rajarathnam K. Amara A. Arenzana-Seisdedos F. Virelizier J. Baggiolini M. Sykes B.D. Clark-Lewis I. EMBO J. 1997; 16: 6996-7007Crossref PubMed Scopus (633) Google Scholar) reveals that it has a global fold similar to other chemokines with a flexible N-terminal region followed by a loop, three antiparallel β-strands, and one C-terminal α-helix. Interest in SDF-1 has grown since CXCR4 was identified as a co-receptor for syncytia-inducing forms of HIV in CD4+ T-cells. Through interaction with CXCR4, SDF-1 inhibits replication of the syncytia-inducing form (T-tropic) of HIV-1 (7Bleul C. Farzan M. Choe H. Parolin C. Clark-Lewis I. Sodroski J. Springer T.A. Nature. 1996; 382: 829-832Crossref PubMed Scopus (1751) Google Scholar, 8Oberlin E. Amara A. Bachelerie F. Bessia C. Virelizier J. Arenzana-Seisdedos F. Schwartz O. Heard J. Clark-Lewis I. Legler D.F. Loetscher M. Baggiolini M. Moser B. Nature. 1996; 382: 833-835Crossref PubMed Scopus (1482) Google Scholar). SDF-1 also appears to be important for attracting mature lymphocytes to the bone marrow. Antagonism of this function before the harvest of the bone marrow for transplantation could be clinically beneficial (16Bleul C.C. Fuhlbrigge R.C. Casasnovas J.M. Aiuti A. Springer T.A. J. Exp. Med. 1996; 184: 1101-1109Crossref PubMed Scopus (1284) Google Scholar). In addition, SDF-1 receptors are coupled to multiple G-proteins that may be important for of natural killer cells (3Maghazachi A. Al-Aoukaty A. FASEB J. 1998; 12: 913-924Crossref PubMed Scopus (59) Google Scholar). SDF-1 an important role in the immune system and may be important for the treatment of AIDS and in bone marrow transplantation. for SDF-1 could a possible in these has recently been in the CXC class of chemokines that important residues for receptor are at the N terminus and the region the two disulfide (14Clark-Lewis I. Kim K. Rajarathnam K. Gong J. Dewald B. Moser B. Baggiolini M. Sykes B.D. J. Leukocyte Biol. 1995; 57: 703-711Crossref PubMed Scopus (336) Google Scholar, P. Gong J. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1998; 273: 22279-22283Abstract Full Text Full Text PDF PubMed Scopus (128) Google M.P. Gong J. Loetscher P. Rajarathnam K. Amara A. Arenzana-Seisdedos F. Virelizier J. Baggiolini M. Sykes B.D. Clark-Lewis I. EMBO J. 1997; 16: 6996-7007Crossref PubMed Scopus (633) Google Scholar, I. C. Baggiolini M. Moser B. J. Biol. Chem. Full Text PDF PubMed Google Scholar, I. Dewald B. T. Moser B. Baggiolini M. Sci. 90: PubMed Scopus Google Scholar, I. Dewald B. Loetscher M. Moser B. Baggiolini M. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, G. N. I. L. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), with the N terminus the receptor (14Clark-Lewis I. Kim K. Rajarathnam K. Gong J. Dewald B. Moser B. Baggiolini M. Sykes B.D. J. Leukocyte Biol. 1995; 57: 703-711Crossref PubMed Scopus (336) Google Scholar). is therefore to suggest that the N terminus could be for activity. These two sites in the structure of SDF-1 (18Crump M.P. Gong J. Loetscher P. Rajarathnam K. Amara A. Arenzana-Seisdedos F. Virelizier J. Baggiolini M. Sykes B.D. Clark-Lewis I. EMBO J. 1997; 16: 6996-7007Crossref PubMed Scopus (633) Google Scholar). short N-terminal peptides of SDF-1 to have SDF-1 (15Loetscher P. Gong J. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1998; 273: 22279-22283Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). This is a and important to residues 1–9 1–9 and 1–17 bind to CXCR4 and and in was determined that the 1–17 and 1–9 dimer peptides similar in of receptor the and 1–9 peptides The 1–9 dimer the of the peptides with SDF-1 with the 1–9 and peptides activity. The for the of the 1–9 dimer an 1–9 similar to that of the 1–9 dimer as a receptor (15Loetscher P. Gong J. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1998; 273: 22279-22283Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). in the structure of the N-terminal region has significant (18Crump M.P. Gong J. Loetscher P. Rajarathnam K. Amara A. Arenzana-Seisdedos F. Virelizier J. Baggiolini M. Sykes B.D. Clark-Lewis I. EMBO J. 1997; 16: 6996-7007Crossref PubMed Scopus (633) Google Scholar), it is of to see there is a conformation of these peptides that the receptor structural on the 1–9 dimer as as the using spectroscopy at the 1–9 dimer and peptides are of the of structures the a major family that of a β-turn structural This was in the structure of SDF-1. These the structuring of the peptides that may be important for recognition in receptor binding. By the structural necessary for receptor we to be to that are of the The N-terminal of SDF-1 and by and by The 1–9 dimer was by the 1–9 in at The was for and of was by and The by in of or and 1 to a of approximately was to a of 1 as an chemical shift The was to using and for to with for for the 1–9 1–9 and 1–17 peptides at using a and at The sequence M. V. V. J. 1992; PubMed Scopus Google Scholar) was for for in for at and to NOE which to be to spectroscopy for the 9-mer with of and with for the of the NOE because approximately to this and this to for The using a of between the of the The NOE as and to of and for with on the 9-mer dimer and 17-mer using the the in Scholar) at an of with high and The structure was an and the target function only for and a for The using the NOE The 9-mer dimer was also to the as in J. Biol. PubMed Scopus Google of structures by the of residues 5–8 one and the A.L. 1996; PubMed Scopus Google Scholar). N-terminal of which to have SDF-1 (15Loetscher P. 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The 9-mer and 9-mer dimer have chemical for which is in and that of the dimer have the conformation but with of residues of the 17-mer are to of the 9-mer and 9-mer dimer possible because of the three the 9-mer 9-mer and the than and than that these residues could of a of These could therefore be in the structure The region of the of the 9-mer dimer and to of is shown in 1 A. of the 9-mer dimer range and and to the of are shown in 1 B. for the 9-mer dimer to because there was of this was the for residues 1–9 of the 17-mer and similar for the 9-mer of and range NOE for the 9-mer dimer and 17-mer are in of and range NOE and for the SDF-1 1–9 dimer and the SDF-1 17-mer as by NOE are by between with the the for in the suggest the of a β-turn conformation for the 9-mer dimer and 17-mer residues and The of a β-turn is and the to the residue in the for the 9-mer dimer and 17-mer a M.D. Krangel M.S. Crit. Rev. Immunol. 1992; 12: 17-46PubMed Google Scholar, 4Bacon K.B. Schall T.J. Int. Arch. 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J. 1995; PubMed Scopus Google Scholar) to to Refs. G. P.E. J. 1995; PubMed Scopus Google Scholar and Liu H. J. Chem. 1997; Scopus Google a of the for the 9-mer dimer and 17-mer The the of between and of proteins. the of the residues in the 9-mer dimer and 17-mer are that these are to Liu H. J. Chem. 1997; Scopus Google Scholar), peptides that are at and have a of the in the to In addition, the a correlation than and significant and for of the 9-mer the of the for residues 5–8 is with of (for the the was with an of the residues 5–8 a of with of residues 11–14 a of with an of for the the was with an The and are shown in The chemical shift for residues 5–8 in the 9-mer dimer and In addition, residues in the 17-mer chemical shift and 1 chemical shift for derived at with chemical shift as in Refs. Liu H. J. Chem. 1997; Scopus Google Scholar and A. Sykes B.D. J. 1995; PubMed Scopus Google for chemical at and chemical shift at A. Sykes B.D. J. 1995; PubMed Scopus Google in a for derived at with chemical shift as in Refs. Liu H. J. Chem. 1997; Scopus Google Scholar and A. Sykes B.D. J. 1995; PubMed Scopus Google for chemical at and chemical shift at A. Sykes B.D. J. 1995; PubMed Scopus Google and to for of the 9-mer structure of the and or using a Scholar) for the 9-mer dimer and 17-mer a family of structures was with the and NOE of than of structures using the A.L. 1996; PubMed Scopus Google Scholar) and NOE for Residues Residues NOE was with a with a of was with a of 4 to their in the in a NOE was with a with a of was with a of 4 to their in the the 9-mer structures of major family of which to of the was by the of residues 5–8 one the 9-mer the was to be other of of than of the R.A. R. J.M. J. 1996; PubMed Scopus Google Scholar) was to that residues in the major in The of the of the residues in the the major was also in of the The is a that a of 1 a is in member of the structure family and the is the for this are in the the major family of structures at has the as for and for with of for and for This is as a β-αR by the of and M.S. G. Sci. 1992; PubMed Scopus Google Scholar, C.M. J.M. PubMed Scopus Google Scholar), with bond in the of residues 5–8 of the residues 5–8 of the structure (residues are is in 1 and for the 9-mer and for residues the structures the major family determined by residues in a and for residues the structures the major family determined by residues was to find the conformation of the peptides that may be by CXCR4. it is likely that the peptides between several it is that the an of these will a the of the J. Biol. PubMed Scopus Google Scholar) on the 9-mer dimer The of structures using using structures starting with the structures by These structures as of The of the structures with a deviation of for residues 5–8 The fold is similar to was using with a in the of with of the 17-mer of the structures of with NOE of than was with the of A.L. 1996; PubMed Scopus Google Scholar) by residues major family of structures with of was the the the at residues 5–8 are similar to that for the 9-mer In addition, the are the β-αR as in the 9-mer the of a structure in the was by residues This a major family of the with a of The of residues 11–14 in the major family are and that and an conformation in of the The of and are and the of residues 11–14 of residues 11–14 of the structure is in the structure is with the first the conformation of the conformation of the The conformation of the appears to be 1 and for the and for residues the structures the major family determined by residues and for residues the structures in the major family determined by residues in a and for residues the structures the major family determined by residues and for residues the structures in the major family determined by residues chemokines in the CC and CXC to it has been shown that the important residues for receptor and in the N-terminal region and the the first two in the sequence D.R. D.R. 1997; PubMed Scopus Google Scholar, T. A. Liu H. Y. Y. PubMed Scopus Google Scholar, B. Dewald B. L. C. Baggiolini M. Clark-Lewis I. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). SDF-1 is and there have been studies of SDF-1 N-terminal peptides (15Loetscher P. Gong J. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1998; 273: 22279-22283Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). the N terminus appears in the structure (18Crump M.P. Gong J. Loetscher P. Rajarathnam K. Amara A. Arenzana-Seisdedos F. Virelizier J. Baggiolini M. Sykes B.D. Clark-Lewis I. EMBO J. 1997; 16: 6996-7007Crossref PubMed Scopus (633) Google Scholar), we to structure in that for the high and of these N-terminal that a conformation it could a starting point for synthesizing non-peptide analogs to act as or of SDF-1 activity. three a 9-mer a 9-mer and a for the 9-mer dimer and 17-mer as as for the 9-mer The of the 1–9 dimer is fold than the 1–9 there are similar in the 1–9 with the in the 1–9 a similar structure be in the 1–9 The of the 1–9 could be to the that there are two sites on the receptor that to be and the 1–9 sites is that there is to the to the first and because of the of the of the to bind to the the of the dimer could be because there is the of the 1–9 that can in and of the the 17-mer binds than the 9-mer the is likely and the recently for SDF-1 receptor and (18Crump M.P. Gong J. Loetscher P. Rajarathnam K. Amara A. Arenzana-Seisdedos F. Virelizier J. Baggiolini M. Sykes B.D. Clark-Lewis I. 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Casasnovas J.M. Aiuti A. Springer T.A. J. Exp. Med. 1996; 184: 1101-1109Crossref PubMed Scopus (1284) Google Scholar, M. Nakano T. Inazawa J. Tashiro K. Tada H. Shinohara T. Honjo T. Genomics. 1995; 28: 495-500Crossref PubMed Scopus (536) Google Scholar) that the CXC The of the N-terminal region is to the receptor has been that SDF-1 N-terminal peptides the of a region for their (15Loetscher P. Gong J. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1998; 273: 22279-22283Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). The in that these peptides are to specific The three-dimensional of the 9-mer dimer and 17-mer determined by spectroscopy at the structure using There appears to be a β-turn by residues 5–8 of the 1–9 dimer and 17-mer peptides with the of a and In addition, the 17-mer a β-turn structural residues this β-turn structural is in the 9-mer dimer and an of several was by using the that one major conformation was at was by the of the chemical shift deviation The of peptides in have correlation than and in the to The and correlation for residues 5–8 of the 9-mer dimer and the 17-mer these residues 11–14 of the 17-mer to of the have significant chemical shift that have a conformation at In the residues correlation for the 9-mer dimer the there was for at the it is likely to the that the which is of the β-αR have a bond These structural motifs may have been in the SDF-1 because are in the SDF-1 The likely is that the structural is in but because for the for the as with the The correlation is to the of The NOE is a function of the correlation which is for flexible parts of the and to in the of the in the SDF-1 and to be for structure because of the of it that these could be for structuring in the flexible of a The SDF-1 1–17 has a similar to the 9-mer dimer (15Loetscher P. Gong J. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1998; 273: 22279-22283Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). that it the β-αR by residues 5–8 in the 1–9 dimer as as a β-turn residues 11–14 This β-turn is similar to that in the SDF-1 and of residues 11–14 in the structure with 11–14 of the results in a deviation of the of residues and in the chemical shift and to similar β-turn in that two are for to the receptor. has been shown that this β-αR is in the conformation of the peptides in in addition, the major for SDF-1 have been H. Y. T. R. K. A. A. T. N. H. N. 1998; PubMed Scopus Google of peptides be of because of the high and the of in or this to the recently of a CC chemokine receptor J. M. W. K. S. I. G.P. A. M. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). that the structural studies of peptides with SDF-1 that are in this may to the of non-peptide that will this structure and bind to CXCR4 with and