β2 (CD18) Mutations Abolish Ligand Recognition by I Domain Integrins LFA-1 ( αLβ2, CD11a/CD18) and MAC-1 ( αMβ2, CD11b/CD18)

Bajt, Mary Lynn; Goodman, Tom; McGuire, Sarah Lea

doi:10.1074/jbc.270.1.94

Cited by 86 publications

(72 citation statements)

References 54 publications

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“…Mutations of Thr206 of C D l l a or the corresponding Thr209 of C D l l b abrogated binding activities (Kamata et al, 1995), and substitution of Ala for Aspl40, Asp140/Ser142, Ser142 or Ser144 in C D l l b did the same (McGuire and Bajt, 1995). Likewise, mutations of Asp137 and Asp239 in CDlla abolished its ICAM-1 binding capacity (Edwards et al, 1995).…”

Section: Structure Of P-integrinsmentioning

confidence: 94%

“…The DXSXS part of the MIDAS motif is completely conserved in the different integrin /?-subunits, but no structural information for other integlin subunits is yet available. Ala substitution of Asp134 or Ser136 in CD18 also abolished binding activity of both CD1 la/ CD18 and CDllbKD18 integrins (Bajt et al, 1995), and mutation of Ser138 resulted in loss of iC3b binding (Zhang and Plow, 1996).…”

Section: Structure Of P-integrinsmentioning

confidence: 99%

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Leukocyte Adhesion

Gahmberg

Tolvanen

Kotovuori

1997

European Journal of Biochemistry

207

191

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Leukocyte adhesion is of pivotal functional importance and this has resulted in extensive research and rapid develonient in the field. Leukocyte adhesion involves members of three molecular families: integrins, members of the immunoglobulin superfatnily and carbohydrate binding selectins and sialoadhesins. Recently, considerable structural information on leukocyte integrins and members of the immunoglobulin superfrtinily of adhesion molecules has been obtained. This fact. combined with the identification of several novel adhesion molecules. has increased our understanding o f how they function at the molecular level. Furthermore, the important issue of how integrins are activated to become adhesive is rapidly advancing,.. It is clearly evident that the knowledge accuniulated from basic research will increasingly be applied in clinical medicine. In this review we focus on two iinportant families of adhesion molecules. Norc. This Review will be reprinted in EJR Kei?cw.\ 1997 which will be av;iil;ible in April I99X.A number of different leukocytes are known and most probably more subgroups will be found concomitantly with the development in typing procedures. 111 addition, the cells rnay represent different stages of differentiation. An individual leukocyte m 11 s t be able to interact with a number of fundamentally different cells. often modified in various ways. and sometimes with the extracellular matrix or foreign microbes. These facts may partially be the reason that many different leukocyte adhesion systems and molecules exist. In addition i t is certainly useful for the organism to have a certain redundancy i n adhcsion molecule expression and function. which could seciire vital functions cven if some adhesion functions are lost or weakened.Cellular immunology used to be largely phenomenal and not inolecular. But with the development of monoclonal antibody and inolecular cloning techniques, combined with the rapid advance in structural elucidation. present day immunology is certainly ii molecular science, and in inany respects in the forefiont of modern biomedical research. In fact, a number of dcvelopinents in other fields of present day biomedical research originate from breakthroughs in iinmunology. and an excellent exaniple is leukocyte adhesion. Although much remains poorly understood, adhesion receptor-ligand interactions are now appreciated to such an extent that much can be applied t o several other areas of research.But research on leiikocytc adhesion is not rewarding only from a basic point of view. Undoubtedly. the large interest in this field steins from iiuinerous potential clinical applications. Many of the iniljor diseases affecting mankind. like cardiovnscular disease. stroke, chronic and iicute inflammations. cancer. malaria, and inany bacterial and viral infections directly involve leukocyte adhesion molecules. Therefore. it comes as no surprise

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Section: Structure Of P-integrinsmentioning

confidence: 94%

Section: Structure Of P-integrinsmentioning

confidence: 99%

Leukocyte Adhesion

Gahmberg

Tolvanen

Kotovuori

1997

European Journal of Biochemistry

207

191

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“…Murine monoclonal antibodies (mAbs) against ␣ M were used as purified IgG fractions: 3H5 [31], LM2/1 [36], and 2LPM19c [37]. The murine monoclonal anti-␣ M antibody 904 [19] was used as culture supernatant.…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

“…The murine monoclonal anti-␣ M antibody 904 [19] was used as culture supernatant. Also used as purified IgG fractions were the anti-␤ 2 murine monoclonals 2D8 [32], 8H1 [31], and TS1/18 [38]. Purified anti-␤ 2 murine monoclonal, mAb R15.7, was kindly provided by R. Rothlein (Boehringer Ingelheim, Ridgefield, CT) [39].…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

“…However, ligand binding function of integrins is not solely dependent on the ␣ subunit. We [31,32] and others [33] have shown through mutational analysis that residues Asp 134 , Ser 136 , Ser 138 , Asp 231 , and Glu 234 of the ␤ 2 subunit are essential for ligand binding of ␣ M ␤ 2 and ␣ L ␤ 2 . These residues are located within a highly conserved region of the integrin ␤ subunits.…”

Section: Introductionmentioning

confidence: 99%

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Expression of a structural domain of the β2 subunit essential for αMβ2 ligand recognition

Goodman¹,

DeGraaf²,

Fischer³

et al. 1998

Journal of Leukocyte Biology

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Expression of the H52 epitope on the β2 subunit is dependent on its interaction with the α subunits of the leukocyte integrins LFA-1, Mac-1 and p150,95 and the presence of Ca2+

Al‐Shamkhani

Law

1998

Eur. J. Immunol.

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Integrin-mediated adhesion is a divalent cation-dependent process. Whether divalent cations directly participate in ligand binding or exert their effects indirectly by affecting the overall structure of the integrin heterodimers is not known. In this study we describe the epi-tope of the mAb H52 which has been mapped to a predicted disulfide-bonded loop (C386 and C400) in the g 2 integrin subunit. In the presence of Ca 2+ and Mg 2+ , the H52 epitope is expressed on the monomeric g 2 subunit, the LFA-1 and Mac-1 heterodimers but not on p150,95, thus implying that this epitope is masked in p150,95. However, expression of the H52 epitope on Mac-1, but not on LFA-1, or the monomeric g 2 subunit, is dependent on the presence of Ca 2+ , thus suggesting that the chelation of Ca 2+ causes a conformational change in Mac-1 which results in the loss of the epitope. These results suggest that expression of the H52 epitope on the g 2 subunit is dependent on its interaction with the different § sub-units. Since the epitope itself is not required for heterodimer formation nor for ligand binding, occupancy of a Ca 2+ binding site(s) must therefore affect the § g subunit interactions, and thus the overall conformation of Mac-1.

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β2 (CD18) Mutations Abolish Ligand Recognition by I Domain Integrins LFA-1 ( αLβ2, CD11a/CD18) and MAC-1 ( αMβ2, CD11b/CD18)

Cited by 86 publications

References 54 publications

Leukocyte Adhesion

Leukocyte Adhesion

Expression of a structural domain of the β2 subunit essential for αMβ2 ligand recognition

Expression of the H52 epitope on the β2 subunit is dependent on its interaction with the α subunits of the leukocyte integrins LFA-1, Mac-1 and p150,95 and the presence of Ca2+

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