SELECTION OF AN RNA MOLECULE THAT MIMICS A MAJOR AUTOANTIGENIC EPITOPE OF HUMAN INSULIN-RECEPTOR

被引:68
作者
DOUDNA, JA [1 ]
CECH, TR [1 ]
SULLENGER, BA [1 ]
机构
[1] UNIV COLORADO, HOWARD HUGHES MED INST, DEPT CHEM & BIOCHEM, BOULDER, CO 80309 USA
关键词
ANTIBODY-RNA INTERACTION; AUTOIMMUNITY; IN VITRO SELECTION; RNA STRUCTURE;
D O I
10.1073/pnas.92.6.2355
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Autoimmunity often involves the abnormal targeting of self-antigens by antibodies, leading to tissue destruction and other pathologies. This process could potentially be disrupted by small ligands that bind specifically to autoantibodies and inhibit their interaction with the target antigen. Here we report the identification of an RNA sequence that binds a mouse monoclonal antibody specific for an autoantigenic epitope of human insulin receptor. The RNA ligand binds specifically and with high affinity (apparent Kd similar or equal to 2 nM) to the anti-insulin receptor antibody and not to other mouse IgGs. The RNA can also act as a decoy, blocking the antibody from binding the insulin receptor. Thus, it probably binds near the combining site on the antibody. Strikingly, the RNA cross-reacts with autoantibodies from patients with extreme insulin resistance. One simple explanation is that the selected RNA may structurally mimic the antigenic epitope on the insulin receptor protein. These results suggest that decoy RNAs may be useful in the treatment of autoimmune diseases.
引用
收藏
页码:2355 / 2359
页数:5
相关论文
共 33 条
  • [1] HIV-1 REV REGULATION INVOLVES RECOGNITION OF NON-WATSON-CRICK BASE-PAIRS IN VIRAL-RNA
    BARTEL, DP
    ZAPP, ML
    GREEN, MR
    SZOSTAK, JW
    [J]. CELL, 1991, 67 (03) : 529 - 536
  • [2] 3 SMALL RIBOOLIGONUCLEOTIDES WITH SPECIFIC ARGININE SITES
    CONNELL, GJ
    ILLANGESEKARE, M
    YARUS, M
    [J]. BIOCHEMISTRY, 1993, 32 (21) : 5497 - 5502
  • [3] THE HUMAN INSULIN-RECEPTOR CDNA - THE STRUCTURAL BASIS FOR HORMONE-ACTIVATED TRANSMEMBRANE SIGNALING
    EBINA, Y
    ELLIS, L
    JARNAGIN, K
    EDERY, M
    GRAF, L
    CLAUSER, E
    OU, JH
    MASIARZ, F
    KAN, YW
    GOLDFINE, ID
    ROTH, RA
    RUTTER, WJ
    [J]. CELL, 1985, 40 (04) : 747 - 758
  • [4] INVITRO SELECTION OF RNA MOLECULES THAT BIND SPECIFIC LIGANDS
    ELLINGTON, AD
    SZOSTAK, JW
    [J]. NATURE, 1990, 346 (6287) : 818 - 822
  • [5] INSULIN-RECEPTOR TYROSINE KINASE STRUCTURE AND FUNCTION
    ELLIS, L
    TAVARE, JM
    LEVINE, BA
    [J]. BIOCHEMICAL SOCIETY TRANSACTIONS, 1991, 19 (02) : 426 - 432
  • [6] STEREOSPECIFIC RECOGNITION OF TRYPTOPHAN AGAROSE BY INVITRO SELECTED RNA
    FAMULOK, M
    SZOSTAK, JW
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1992, 114 (10) : 3990 - 3991
  • [7] ANTIBODIES THAT IMPAIR INSULIN RECEPTOR-BINDING IN AN UNUSUAL DIABETIC SYNDROME WITH SEVERE INSULIN RESISTANCE
    FLIER, JS
    KAHN, CR
    ROTH, J
    BAR, RS
    [J]. SCIENCE, 1975, 190 (4209) : 63 - 65
  • [8] MONOCLONAL-ANTIBODIES TO THE HUMAN INSULIN-RECEPTOR THAT ACTIVATE GLUCOSE-TRANSPORT BUT NOT INSULIN-RECEPTOR KINASE-ACTIVITY
    FORSAYETH, JR
    CARO, JF
    SINHA, MK
    MADDUX, BA
    GOLDFINE, ID
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (10) : 3448 - 3451
  • [9] FORSAYETH JR, 1987, J BIOL CHEM, V262, P4134
  • [10] IMPROVED PREDICTIONS OF SECONDARY STRUCTURES FOR RNA
    JAEGER, JA
    TURNER, DH
    ZUKER, M
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (20) : 7706 - 7710