Crystal structure of MHC class II-associated p41 Ii fragment bound to cathepsin L reveals the structural basis for differentiation between cathepsins L and S

被引:176
作者
Guncar, G [1 ]
Pungercic, G [1 ]
Klemencic, I [1 ]
Turk, V [1 ]
Turk, D [1 ]
机构
[1] Jozef Stefan Inst, Dept Biochem & Mol Biol, SLO-1000 Ljubljana, Slovenia
关键词
cathepsin; crystal structure; invariant chain; MHC class II; thyroglobulin type-1 domain;
D O I
10.1093/emboj/18.4.793
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 lysosomal cysteine proteases cathepsins S and L play crucial roles in the degradation of the invariant chain during maturation of MHC class II molecules and antigen processing. The p41 form of the invariant chain includes a fragment which specifically inhibits cathepsin L but not S, The crystal structure of the p41 fragment, a homologue of the thyroglobulin type-1 domains, has been determined at 2.0 Angstrom resolution in complex with cathepsin L, The structure of the p41 fragment demonstrates a novel fold, consisting of two subdomains, each stabilized by disulfide bridges. The first subdomain is an alpha-helix-beta-strand arrangement, whereas the second subdomain has a predominantly beta-strand arrangement. The wedge shape and three-loop arrangement of the p41 fragment bound to the active site cleft of cathepsin L are reminiscent of the inhibitory edge of cystatins, thus demonstrating the first example of convergent evolution observed in cysteine protease inhibitors. However, the different fold of the p41 fragment results in additional contacts with the top of the R-domain of the enzymes, which defines the specificity-determining S2 and S1' substrate-binding sites. This enables inhibitors based on the thyroglobulin type-1 domain fold, in contrast to the rather non-selective cystatins, to exhibit specificity for their target enzymes.
引用
收藏
页码:793 / 803
页数:11
相关论文
共 64 条
  • [31] SEQUENCE INVESTIGATION OF THE MAJOR GASTROINTESTINAL TUMOR-ASSOCIATED ANTIGEN GENE FAMILY, GA733
    LINNENBACH, AJ
    WOJCIEROWSKI, J
    WU, SA
    PYRC, JJ
    ROSS, AH
    DIETZSCHOLD, B
    SPEICHER, D
    KOPROWSKI, H
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (01) : 27 - 31
  • [32] Phylogenetic survey of soluble saxitoxin-binding activity in pursuit of the function and molecular evolution of saxiphilin, a relative of transferrin
    Llewellyn, LE
    Bell, PM
    Moczydlowski, EG
    [J]. PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 1997, 264 (1383) : 891 - 902
  • [33] MALTHIERY Y, 1987, EUR J BIOCHEM, V165, P314
  • [34] Crystal structure of human cathepsin S
    McGrath, ME
    Palmer, JT
    Brömme, D
    Somoza, JR
    [J]. PROTEIN SCIENCE, 1998, 7 (06) : 1294 - 1302
  • [35] LONELY MHC MOLECULES SEEKING IMMUNOGENIC PEPTIDES FOR MEANINGFUL RELATIONSHIPS
    MELLMAN, I
    PIERRE, P
    AMIGORENA, S
    [J]. CURRENT OPINION IN CELL BIOLOGY, 1995, 7 (04) : 564 - 572
  • [36] Raster3D: Photorealistic molecular graphics
    Merritt, EA
    Bacon, DJ
    [J]. MACROMOLECULAR CRYSTALLOGRAPHY, PT B, 1997, 277 : 505 - 524
  • [37] Characterization of the type-1 repeat from thyroglobulin, a cysteine-rich module found in proteins from different families
    Molina, F
    Bouanani, M
    Pau, B
    Granier, C
    [J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 1996, 240 (01): : 125 - 133
  • [38] The type-1 repeats of thyroglobulin regulate thyroglobulin degradation and T3, T4 release in thyrocytes
    Molina, F
    Pau, B
    Granier, C
    [J]. FEBS LETTERS, 1996, 391 (03) : 229 - 231
  • [39] MOLECULAR-CLONING OF BULLFROG SAXIPHILIN - A UNIQUE RELATIVE OF THE TRANSFERRIN FAMILY THAT BINDS SAXITOXIN
    MORABITO, MA
    MOCZYDLOWSKI, E
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (07) : 2478 - 2482
  • [40] THE REFINED 2.15-A X-RAY CRYSTAL-STRUCTURE OF HUMAN LIVER CATHEPSIN-B - THE STRUCTURAL BASIS FOR ITS SPECIFICITY
    MUSIL, D
    ZUCIC, D
    TURK, D
    ENGH, RA
    MAYR, I
    HUBER, R
    POPOVIC, T
    TURK, V
    TOWATARI, T
    KATUNUMA, N
    BODE, W
    [J]. EMBO JOURNAL, 1991, 10 (09) : 2321 - 2330