Influence of interleukin-6 (IL-6) dimerization on formation of the high affinity hexameric IL-6 receptor complex

被引:48
作者
Ward, LD
Hammacher, A
Howlett, GJ
Matthews, JM
Fabri, L
Moritz, RL
Nice, EC
Weinstock, J
Simpson, RJ
机构
[1] UNIV MELBOURNE,LUDWIG INST CANC RES,WALTER & ELIZA HALL INST MED RES,JOINT PROT STRUCT LAB,PARKVILLE,VIC 3050,AUSTRALIA
[2] UNIV MELBOURNE,DEPT BIOCHEM,PARKVILLE,VIC 3050,AUSTRALIA
[3] LUDWIG INST CANC RES,PARKVILLE,VIC 3050,AUSTRALIA
关键词
D O I
10.1074/jbc.271.33.20138
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The high affinity interleukin-6 (IL-6) signaling complex consists of IL-6 and two membrane-associated receptor components: a low affinity but specific IL-6 receptor and the affinity converter/signal transducing protein gp130. Monomeric (IL-6(M)) and dimeric (IL-6(D)) forms of Escherichia coli-derived human IL-6 and the extracellular (''soluble'') portions of the IL-6 receptor (sIL-6R) and gp130 have been purified in order to investigate the effect of IL-6 dimerization on binding to the receptor complex. Although IL-6(D) has a higher binding affinity for immobilized sIL-6R, as determined by biosensor analysis employing surface plasmon resonance detection, IL-6(M) is more potent than IL-6(D) in a STAT3 phosphorylation assay. The difference in potency is significantly less pronounced when measured in the murine 7TD1 hybridoma growth factor assay and the human hepatoma HepG2 bioassay due to time-dependent dissociation of 37 degrees C of IL-6 dimers into active monomers. The increased binding affinity of IL-6(D) appears to be due to its ability to cross-link two sIL-6R molecules on the biosensor surface. Studies of the IL-6 ternary complex formation demonstrated that the reduced biological potency of IL-6(D) resulted from a decreased ability of the IL-6(D) .(sIL-6R)(2) complex to couple with the soluble portion of gp130. These data imply that the IL-6-induced dimerization of sIL-6R is not the driving force in promoting formation of the hexameric (IL-6 . IL-6R . gp130)(2) complex. A model is presented whereby the trimeric complex of IL-6R, pg130, and IL-6(M) forms before the functional hexamer. Due to its increased affinity for the IL-6R but its decreased ability to couple with gp130, we suggest that a stable IL-6 dimer may be an efficient IL-6 antagonist.
引用
收藏
页码:20138 / 20144
页数:7
相关论文
共 38 条
  • [21] IL-6-INDUCED HOMODIMERIZATION OF GP-130 AND ASSOCIATED ACTIVATION OF A TYROSINE KINASE
    MURAKAMI, M
    HIBI, M
    NAKAGAWA, N
    NAKAGAWA, T
    YASUKAWA, K
    YAMANISHI, K
    TAGA, T
    KISHIMOTO, T
    [J]. SCIENCE, 1993, 260 (5115) : 1808 - 1810
  • [22] Narazaki M., 1994, GUIDEBOOK CYTOKINES, P56
  • [23] DETERMINATION OF RATE AND EQUILIBRIUM BINDING CONSTANTS FOR MACROMOLECULAR INTERACTIONS USING SURFACE-PLASMON RESONANCE - USE OF NONLINEAR LEAST-SQUARES ANALYSIS-METHODS
    OSHANNESSY, DJ
    BRIGHAMBURKE, M
    SONESON, KK
    HENSLEY, P
    BROOKS, I
    [J]. ANALYTICAL BIOCHEMISTRY, 1993, 212 (02) : 457 - 468
  • [24] 2 DISTINCT AND INDEPENDENT SITES ON IL-6 TRIGGER GP130 DIMER FORMATION AND SIGNALING
    PAONESSA, G
    GRAZIANI, R
    DESERIO, A
    SAVINO, R
    CIAPPONI, L
    LAHM, A
    SALVATI, AL
    TONIATTI, C
    CILIBERTO, G
    [J]. EMBO JOURNAL, 1995, 14 (09) : 1942 - 1951
  • [25] CARDIOTROPHIN-1 - BIOLOGICAL-ACTIVITIES AND BINDING TO THE LEUKEMIA INHIBITORY FACTOR-RECEPTOR GP130 SIGNALING COMPLEX
    PENNICA, D
    SHAW, KJ
    SWANSON, TA
    MOORE, MW
    SHELTON, DL
    ZIONCHECK, KA
    ROSENTHAL, A
    TAGA, T
    PAONI, NF
    WOOD, WI
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (18) : 10915 - 10922
  • [26] ROSEJOHN S, 1991, J BIOL CHEM, V266, P3841
  • [27] ASSOCIATION AND ACTIVATION OF JAK-TYK KINASES BY CNTF-LIF-OSM-IL-6 BETA-RECEPTOR COMPONENTS
    STAHL, N
    BOULTON, TG
    FARRUGGELLA, T
    IP, NY
    DAVIS, S
    WITTHUHN, BA
    QUELLE, FW
    SILVENNOINEN, O
    BARBIERI, G
    PELLEGRINI, S
    IHLE, JN
    YANCOPOULOS, GD
    [J]. SCIENCE, 1994, 263 (5143) : 92 - 95
  • [28] QUANTITATIVE-DETERMINATION OF SURFACE CONCENTRATION OF PROTEIN WITH SURFACE-PLASMON RESONANCE USING RADIOLABELED PROTEINS
    STENBERG, E
    PERSSON, B
    ROOS, H
    URBANICZKY, C
    [J]. JOURNAL OF COLLOID AND INTERFACE SCIENCE, 1991, 143 (02) : 513 - 526
  • [29] RECOMBINANT SOLUBLE HUMAN INTERLEUKIN-6 RECEPTOR - EXPRESSION IN ESCHERICHIA-COLI, RENATURATION AND PURIFICATION
    STOYAN, T
    MICHAELIS, U
    SCHOOLTINK, H
    VANDAM, M
    RUDOLPH, R
    HEINRICH, PC
    ROSEJOHN, S
    [J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 1993, 216 (01): : 239 - 245
  • [30] TAGA T, 1992, CRIT REV IMMUNOL, V11, P265