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© The Rockefeller University Press, 0021-9525/2000/6/1485/ $5.00
The Journal of Cell Biology, Volume 149, Number 7, June 26, 2000 1485-1502

Original Article

Plasmin-sensitive Dibasic Sequences in the Third Fibronectin-like Domain of L1–Cell Adhesion Molecule (CAM) Facilitate Homomultimerization and Concomitant Integrin Recruitment

Steve Sillettia,b, Fang Meib, Dean Sheppardc,d, and Anthony M.P. Montgomerya,b
a Department of Pediatrics, University of California at San Diego, La Jolla, California 92037
b Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
c Lung Biology Center, Center for Occupational and Environmental Health, Cardiovascular Research Institute,
d Department of Medicine, University of California, San Francisco, California 94080

Correspondence to: Anthony M.P. Montgomery, Department of Pediatrics-0983, The Whittier Institute, University of California at San Diego, 9894 Genesee Avenue, La Jolla, CA 92037. Tel:(858) 550-2909 Fax:(858) 558-3495 E-mail:ammontgo{at}ucsd.edu.

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}vß3 and {alpha}5ß1. A pep- tide derived from the putative C-C' loop of FN3 (GSQRKHSKRHIHKDHV852) also forms trimeric complexes and supports {alpha}vß3 and {alpha}5ß1 binding. Substitution of the dibasic RK841 and KR845 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{downarrow}HSK{downarrow}RH846. The integrin {alpha}9ß1, 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.

Key Words: neural CAM, heterophilic ligation, melanoma, {alpha}vß3, {alpha}5ß1, {alpha}9ß1


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