CRYSTAL-STRUCTURE OF DIMERIC HUMAN CILIARY NEUROTROPHIC FACTOR DETERMINED BY MAD PHASING

被引:123
作者
MCDONALD, NQ
PANAYOTATOS, N
HENDRICKSON, WA
机构
[1] COLUMBIA UNIV,DEPT BIOCHEM & MOLEC BIOPHYS,NEW YORK,NY 10032
[2] COLUMBIA UNIV,HOWARD HUGHES MED INST,NEW YORK,NY 10032
关键词
CYTOKINE; MULTIWAVELENGTH ANOMALOUS DIFFRACTION; NEUROTROPHIC FACTOR; X-RAY STRUCTURE;
D O I
10.1002/j.1460-2075.1995.tb07269.x
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
Ciliary neurotrophic factor (CNTF) promotes the survival and differentiation of developing motor neurons and is a potential therapeutic for treating neurodegeneration and nerve injury, The crystal structure of human CNTF has been determined at 2.4 Angstrom resolution using multi-wavelength anomalous diffraction (MAD) phasing from a single Yb3+ ion. The structure reveals that CNTF is dimeric, with a novel anti-parallel arrangement of the subunits, not previously observed for other cytokines, Each subunit adopts a double crossover four-helix bundle fold, in which two helices contribute to the dimer interface, whilst two different helices show pronounced kinks, Analysis of the electrostatic surface of CNTF identified residues within these kinked helices that may contact the CNTF receptor-alpha. Solution experiments show that CNTF dimerizes at concentrations >40 mu M. Such dimers are likely to be relevant to the storage of CNTF in the peripheral nerve given the high concentrations present in this tissue, However, it is unlikely that they play a role in engaging the three distinct receptor subunits that comprise the CNTF receptor, given the low concentration of extracellular CNTF and its high potency.
引用
收藏
页码:2689 / 2699
页数:11
相关论文
共 58 条
  • [1] Adler R, 1993, Curr Opin Neurobiol, V3, P785, DOI 10.1016/0959-4388(93)90154-Q
  • [2] [Anonymous], 1994, ACTA CRYSTALLOGR D, V50, P760
  • [3] CRYSTAL-STRUCTURE OF INTERLEUKIN-8 - SYMBIOSIS OF NMR AND CRYSTALLOGRAPHY
    BALDWIN, ET
    WEBER, IT
    STCHARLES, R
    XUAN, JC
    APPELLA, E
    YAMADA, M
    MATSUSHIMA, K
    EDWARDS, BFP
    CLORE, GM
    GRONENBORN, AM
    WLODAWER, A
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (02) : 502 - 506
  • [4] NEUROPOIETIC CYTOKINES IN THE HEMATOPOIETIC FOLD
    BAZAN, JF
    [J]. NEURON, 1991, 7 (02) : 197 - 208
  • [5] SIGNAL TRANSDUCTION - JUST ANOTHER SIGNALING PATHWAY
    BRISCOE, J
    GUSCHIN, D
    [J]. CURRENT BIOLOGY, 1994, 4 (11) : 1033 - 1035
  • [6] BRUNGER AT, 1992, XPLOR SYSTEM XRAY CR
  • [7] DIMERIZATION OF HUMAN GROWTH-HORMONE BY ZINC
    CUNNINGHAM, BC
    MULKERRIN, MG
    WELLS, JA
    [J]. SCIENCE, 1991, 253 (5019) : 545 - 548
  • [8] LIFR-BETA AND GP-130 AS HETERODIMERIZING SIGNAL TRANSDUCERS OF THE TRIPARTITE CNTF RECEPTOR
    DAVIS, S
    ALDRICH, TH
    STAHL, N
    PAN, L
    TAGA, T
    KISHIMOTO, T
    IP, NY
    YANCOPOULOS, GD
    [J]. SCIENCE, 1993, 260 (5115) : 1805 - 1808
  • [9] RELEASED FORM OF CNTF RECEPTOR-ALPHA COMPONENT AS A SOLUBLE MEDIATOR OF CNTF RESPONSES
    DAVIS, S
    ALDRICH, TH
    IP, NY
    STAHL, N
    SCHERER, S
    FARRUGGELLA, T
    DISTEFANO, PS
    CURTIS, R
    PANAYOTATOS, N
    GASCAN, H
    CHEVALIER, S
    YANCOPOULOS, GD
    [J]. SCIENCE, 1993, 259 (5102) : 1736 - 1739
  • [10] DAVIS S, 1991, SCIENCE, V253, P53