Amino acid residues in the PSI domain and cysteine-rich repeats of the integrin beta2 subunit that restrain activation of the integrin alpha(X)beta(2).
The leukocyte integrin alpha(X)beta(2) (p150,95) recognizes the iC3b complement fragment and functions as the complement receptor type 4. alpha(X)beta(2) is more resistant to activation than other beta(2) integrins and is inactive in transfected cells. However, when human alpha(X) is paired with chicken or mouse beta(2), alpha(X)beta(2) is activated for binding to iC3b. Activating substitutions were mapped to individual residues or groups of residues in the N-terminal plexin/semaphorin/integrin (PSI) domain and C-terminal cysteine-rich repeats 2 and 3. These regions are linked by a long range disulfide bond. Substitutions in the PSI domain synergized with substitutions in the cysteine-rich repeats. Substitutions T4P, T22A, Q525S, and V526L gave full activation. Activation of binding to iC3b correlated with exposure of the CBR LFA-1/2 epitope in cysteine-rich repeat 3. The data suggest that the activating substitutions are present in an interface that restrains the human alpha(X)/human beta(2) integrin in the inactive state. The opening of this interface is linked to structural rearrangements in other domains that activate ligand binding.
Zang
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Center for Blood Research, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Springer
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D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D018821:CD18 Antigens / Q000737:chemistry*; D015815:Cell Adhesion Molecules / Q000737:chemistry; D002460:Cell Line; D002645:Chickens; D003179:Complement C3b / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry*; D004220:Disulfides; D004912:Erythrocytes / Q000378:metabolism; D005434:Flow Cytometry; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D016167:Integrin alphaXbeta2; D016023:Integrins / Q000737:chemistry; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011951:Receptors, Complement / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D000596:Amino Acids; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D004220:Disulfides; D006023:Glycoproteins; D016167:Integrin alphaXbeta2; D016023:Integrins; D008024:Ligands; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011951:Receptors, Complement; C091529:plexin; D003179:Complement C3b; D003545:Cysteine