Plasmin-sensitive dibasic sequences in the third fibronectin-like domain of L1-cell adhesion molecule (CAM) facilitate homomultimerization and concomitant integrin recruitment.
L1 is a multidomain transmembrane neural recognition molecule essential for neurohistogenesis. While moieties in the immunoglobulin-like domains of L1 have been implicated in both heterophilic and homophilic binding, the function of the fibronectin (FN)-like repeats remains largely unresolved. Here, we demonstrate that the third FN-like repeat of L1 (FN3) spontaneously ... homomultimerizes to form trimeric and higher order complexes. Remarkably, these complexes support direct RGD-independent interactions with several integrins, including alpha(v)beta(3) and alpha(5)beta(1). A pep- tide derived from the putative C-C' loop of FN3 (GSQRKHSKRHIHKDHV(852)) also forms trimeric complexes and supports alpha(v)beta(3) and alpha(5)beta(1) binding. Substitution of the dibasic RK(841) and KR(845) sequences within this peptide or the FN3 domain limited multimerization and abrogated integrin binding. Evidence is presented that the multimerization of, and integrin binding to, the FN3 domain is regulated both by conformational constraints imposed by other domains and by plasmin- mediated cleavage within the sequence RK( downward arrow)HSK( downward arrow)RH(846). The integrin alpha(9)beta(1), which also recognizes the FN3 domain, colocalizes with L1 in a manner restricted to sites of cell-cell contact. We propose that distal receptor ligation events at the cell-cell interface may induce a conformational change within the L1 ectodomain that culminates in receptor multimerization and integrin recruitment via interaction with the FN3 domain.
Mesh Terms:
Amino Acid Sequence, Binding Sites, Cell Communication, Cell Membrane, Fibrinolysin, Fibronectins, Humans, Integrins, Leukocyte L1 Antigen Complex, Melanoma, Membrane Glycoproteins, Molecular Sequence Data, Neural Cell Adhesion Molecules, Protein Structure, Tertiary, Receptors, Fibronectin, Receptors, Vitronectin, Repetitive Sequences, Nucleic Acid, Signal Transduction, Tumor Cells, Cultured
Amino Acid Sequence, Binding Sites, Cell Communication, Cell Membrane, Fibrinolysin, Fibronectins, Humans, Integrins, Leukocyte L1 Antigen Complex, Melanoma, Membrane Glycoproteins, Molecular Sequence Data, Neural Cell Adhesion Molecules, Protein Structure, Tertiary, Receptors, Fibronectin, Receptors, Vitronectin, Repetitive Sequences, Nucleic Acid, Signal Transduction, Tumor Cells, Cultured
J. Cell Biol.
Date: Jun. 26, 2000
PubMed ID: 10871287
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