Identification of critical amino-acid residues on the erythroid intercellular adhesion molecule-4 (ICAM-4) mediating adhesion to alpha V integrins.
Intercellular adhesion molecule-4 (ICAM-4, syn. LW glycoprotein) interacts with the integrins alpha(L)beta(2), alpha(M)beta(2), A(4)beta(1), the alpha(V) family, and alpha(IIb)beta(3). Systematic mutagenesis of surface-exposed residues conserved between human and murine ICAM-4 defined 12 single amino-acid changes that affect the interaction of ICAM-4 with alpha(V) integrins. Mutation of 10 of these residues, 8 of which are spatially close on the surface of the molecule, led to a reduction in adhesion. Moreover, peptides corresponding to regions of ICAM-4 involved in its interaction with alpha(V) integrins inhibited these interactions. The other 2 mutations increased the extent of interaction of ICAM-4 with alpha(V) integrins. These mutations appear to prevent glycosylation of N160, suggesting that changes in glycosylation may modulate ICAM-4-alpha(V) integrin interactions. The region of ICAM-4 identified as the binding site for alpha(V) integrins is adjacent to the binding sites for alpha(L)beta(2) and alpha(M)beta(2). Selective binding of ICAM-4 to different integrins may be important for a variety of normal red cell functions and also relevant to the pathology of thrombotic disorders and vasoocclusive events in sickle cell disease. Our findings suggest the feasibility of developing selective inhibitors of ICAM-4-integrin adhesion of therapeutic value in these diseases.
Mankelow
Tosti J
TJ
Bristol Institute for Transfusion Sciences, Southmead Rd, Bristol, BS10 5ND, UK. tosti.mankelow@nbs.nhs.uk
Spring
Frances A
FA
Parsons
Stephen F
SF
Brady
R Leo
RL
Mohandas
Narla
N
Chasis
Joel A
JA
Anstee
David J
DJ
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018983:DNA Footprinting; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism*; D016296:Mutagenesis; D010446:Peptide Fragments / Q000494:pharmacology; D017434:Protein Structure, Tertiary
D015815:Cell Adhesion Molecules; C095100:ICAM4 protein, human; D039564:Integrin alphaV; D010446:Peptide Fragments