The structure of immunoglobulin superfamily domains 1 and 2 of MAdCAM-1 reveals novel features important for integrin recognition

被引:53
作者
Tan, K
Casasnovas, JM
Liu, JH
Briskin, MJ
Springer, TA
Wang, JH
机构
[1] Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[3] LeukoSite Inc, Cambridge, MA 02142 USA
[4] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA
[5] Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
IgSF domain; integrin-binding sites; integrin ligand; MAdCAM-1; X-ray crystallography;
D O I
10.1016/S0969-2126(98)00080-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
Background: Mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is a cell adhesion molecule that is expressed on the endothelium in mucosa, and guides the specific homing of lymphocytes into mucosal tissues. MAdCAM-1 belongs to a subclass of the immunoglobulin superfamily (IgSF), the members of which are ligands for integrins, Human MAdCAM-1 has a unique dual function compared to other members in the same subclass in that it binds both the integrin alpha 4 beta 7, through its two IgSF domains, and a selectin expressed on leukocytes, via carbohydrate sidechains. The structure determination of the two IgSF domains and comparison to the N-terminal two-domain structures of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecules (ICAM-1 and ICAM-2) allow us to assess the molecular basis of the interactions between integrins and their preferred ligands, Results: The crystal structure of a fragment containing the two IgSF domains of human MAdCAM-1 has been determined to 2.2 Angstrom resolution. The structure of MAdCAM-1 reveals two separate integrin-recognition motifs, The key integrin-binding residue, Asp42, resides in the CD loop of domain 1; a buried arginine residue (Arg70) plays a critical role in maintaining the conformation of this loop. The second binding site is associated with an unusual long D strand in domain 2, The D and E strands extend beyond the main body of the domain, forming a negatively charged beta ribbon unique to MAdCAM-1,This ribbon is located on the same face as the key aspartate residue in domain 1, consistent with evidence that it is involved in integrin binding. Conclusions: The structural comparison of MAdCAM-1 to other members of the same IgSF subclass reveals some interesting features. Firstly, MAdCAM-1, like VCAM-1, has the key integrin-binding residue located on the protruding CD loop of domain 1 and binds to an integrin that lacks an I domain, This is in contrast to ICAM-1 and ICAM-2 where the key residue is located at the end of the C strand on a fiat surface and which bind to integrins that contain I domains. Secondly, architectural differences in the CD loops of MAdCAM-1 and VCAM-1 cause an 8 A shift in position of the critical aspartate residue, and may partly determine their binding preference for different integrins, Finally, the unusual charge distribution of the two-domain fragment of MAdCAM-1 is predicted to orient the molecule optimally for integrin binding on the top of its long mucin-like stalk.
引用
收藏
页码:793 / 801
页数:9
相关论文
共 49 条
[1]   THE INTEGRIN VLA-4 SUPPORTS TETHERING AND ROLLING IN FLOW ON VCAM-1 [J].
ALON, R ;
KASSNER, PD ;
CARR, MW ;
FINGER, EB ;
HEMLER, ME ;
SPRINGER, TA .
JOURNAL OF CELL BIOLOGY, 1995, 128 (06) :1243-1253
[2]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[3]   DISTINCT ROLES OF L-SELECTIN AND INTEGRINS ALPHA-4-BETA-7 AND LFA-1 IN LYMPHOCYTE HOMING TO PEYERS PATCH-HEV IN-SITU - THE MULTISTEP MODEL CONFIRMED AND REFINED [J].
BARGATZE, RF ;
JUTILA, MA ;
BUTCHER, EC .
IMMUNITY, 1995, 3 (01) :99-108
[4]   The structure of the two amino-terminal domains of human ICAM-1 suggests how it functions as a rhinovirus receptor and as an LFA-1 integrin ligand [J].
Bella, J ;
Kolatkar, PR ;
Marlor, CW ;
Greve, JM ;
Rossmann, MG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (08) :4140-4145
[5]   L-SELECTIN-MEDIATED LYMPHOCYTE ROLLING ON MADCAM-1 [J].
BERG, EL ;
MCEVOY, LM ;
BERLIN, C ;
BARGATZE, RF ;
BUTCHER, EC .
NATURE, 1993, 366 (6456) :695-698
[6]   ALPHA-4 INTEGRINS MEDIATE LYMPHOCYTE ATTACHMENT AND ROLLING UNDER PHYSIOLOGICAL FLOW [J].
BERLIN, C ;
BARGATZE, RF ;
CAMPBELL, JJ ;
VONANDRIAN, UH ;
SZABO, MC ;
HASSLEN, SR ;
NELSON, RD ;
BERG, EL ;
ERLANDSEN, SL ;
BUTCHER, EC .
CELL, 1995, 80 (03) :413-422
[7]   ALPHA-4-BETA-7-INTEGRIN MEDIATES LYMPHOCYTE BINDING TO THE MUCOSAL VASCULAR ADDRESSIN MADCAM-1 [J].
BERLIN, C ;
BERG, EL ;
BRISKIN, MJ ;
ANDREW, DP ;
KILSHAW, PJ ;
HOLZMANN, B ;
WEISSMAN, IL ;
HAMANN, A ;
BUTCHER, EC .
CELL, 1993, 74 (01) :185-195
[8]  
BORDERS CL, 1994, PROTEIN SCI, V3, P541
[9]  
Briskin M, 1997, AM J PATHOL, V151, P97
[10]  
Briskin MJ, 1996, J IMMUNOL, V156, P719