Abstract
PLEXIN genes encode receptors for secreted and membrane-bound semaphorins. It was proposed that the extracellular domain of plexins acts as an inhibitory moiety, preventing receptor activation. Here we show that plexin-B1 and plexin-B2 undergo proteolytic processing in their extracellular portion, thereby converting single-chain precursors into non-disulfide-linked, heterodimeric receptors. We demonstrate that plexin processing is mediated by subtilisin-like proprotein convertases, by inhibition with alpha1-antitrypsin Portland, and by mutagenesis of the substrate-cleavage sites. We provide evidence indicating that proprotein convertases cleave plexins in a post-Golgi compartment and, likely, at the cell surface. In addition, we find that both cell surface targeting and proteolytic processing of plexin-B1 depend on protein-protein interaction motifs in the cytoplasmic domain of the receptor. We then show that proteolytic conversion of plexin-B1 into a heterodimeric receptor greatly increases the binding and the functional response to its specific ligand semaphorin 4D/CD100. Thus, we conclude that cleavage by proprotein convertases is a novel regulatory step for semaphorin receptors localized at the cell surface.
Highlights
Plexins function as cell surface receptors for all classes of semaphorins, either alone or in complex with neuropilins (Refs. 1– 4, reviewed in Ref. 5)
We demonstrate that plexin processing is mediated by subtilisin-like proprotein convertases, by inhibition with ␣1-antitrypsin Portland, and by mutagenesis of the substrate-cleavage sites
We have previously reported that the human genome contains at least nine different plexin genes (1)
Summary
In addition to mediating ligand binding, it can associate with neuropilins (1, 4) and scatter factor receptors (8) It was reported (9) that deleting part of the extracellular domain of plexins results in a conformational change that activates receptor signaling. The extracellular domains of plexin-B1 and plexin-B2 contain a putative cleavage site for subtilisin-like proprotein convertases, located in the proximity of the transmembrane domain (1). This site is phylogenetically conserved, because it is found in fly plexin B (1). The family of subtilisin-like proprotein convertases (PCs) includes furin and many other members (reviewed in Ref. 10) They are known to process a variety of transmembrane and secreted proteins, including scatter factor receptors and semaphorins, which are both phylogenetically related to plexins. We have shown that the proteolytic processing of plexins by PCs significantly increases ligand binding and functional response
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