Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions

Abstract

Plexin transmembrane receptors and their semaphorin ligands, as well as their co-receptors (Neuropilin, Integrin, VEGFR2, ErbB2, and Met kinase) are emerging as key regulatory proteins in a wide variety of developmental, regenerative, but also pathological processes. The diverse arenas of plexin function are surveyed, including roles in the nervous, cardiovascular, bone and skeletal, and immune systems. Such different settings require considerable specificity among the plexin and semaphorin family members which in turn are accompanied by a variety of cell signaling networks. Underlying the latter are the mechanistic details of the interactions and catalytic events at the molecular level. Very recently, dramatic progress has been made in solving the structures of plexins and of their complexes with associated proteins. This molecular level information is now suggesting detailed mechanisms for the function of both the extracellular as well as the intracellular plexin regions. Specifically, several groups have solved structures for extracellular domains for plexin-A2, -B1, and -C1, many in complex with semaphorin ligands. On the intracellular side, the role of small Rho GTPases has been of particular interest. These directly associate with plexin and stimulate a GTPase activating (GAP) function in the plexin catalytic domain to downregulate Ras GTPases. Structures for the Rho GTPase binding domains have been presented for several plexins, some with Rnd1 bound. The entire intracellular domain structure of plexin-A1, -A3, and -B1 have also been solved alone and in complex with Rac1. However, key aspects of the interplay between GTPases and plexins remain far from clear. The structural information is helping the plexin field to focus on key questions at the protein structural, cellular, as well as organism level that collaboratoria of investigations are likely to answer.

Dynamic control of β1 integrin adhesion by the plexinD1-sema3E axis

“…We propose that plexinD1 per se functions as a scaffold to maintain β1 integrin in clusters. In contrast, sema3E binding initiates cytoskeletal remodeling via modulation of plexinD1-intrinsic or -associated GAP activity, breaking the cytoskeletal stabilization of the activated β1 integrin conformation (5).…”

“…Although plexins harbor potential for regulating small GTPases that mediate cytoskeletal remodeling, either through a direct cytoplasmic GTPase-activating protein (GAP) domain and Rac/Rho-GTPase binding domain or through sequestration of guanidine nucleotide exchange factor (GEF) proteins to the membrane-proximal cytoplasmic face, there is little consensus on plexin signaling pathways in a complex physiological context (5).…”

Genetic dissection of plexin signaling in vivo

“…The activation of plexins by their semaphorin ligands triggers several intracellular signaling cascades, most of which modulate the activity of small GTPases (10). The intracellular domain of all plexins shares homology with GTPase-activating proteins (GAPs) and confers the deactivation of R-Ras, M-Ras, and Rap1 (11)(12)(13)(14)(15)(16)(17).…”

Regulation of dendritic development by semaphorin 3A through novel intracellular remote signaling

“…94 To elucidate the significance of CRMP2 phosphorylation in the pathogenesis of Alzheimer disease, CRMP2 phosphorylation-deficient knock-in (crmp2 ki / ki ) mice were generated in which the serine residue at 522 of the protein was replaced with alanine. Intracerebroventricular injection of Ab [25][26][27][28][29][30][31][32][33][34][35] peptide, a neurotoxic fragment of Ab protein, in wild-type mice increased hippocampal phosphorylation of CRMP2. Behavioral assessment revealed that the injection of the Ab [25][26][27][28][29][30][31][32][33][34][35] peptide caused impairment of both cognitive function and long-term potentiation in wild-type animals, but not in crmp2 ki / ki mice.…”

“…32,33 The plexin extracellular region contains several different motifs and domains, including a divergent sema domain, whereas the intracellular region always contains a GTPase-activating protein (GAP) domain. Unlike type 3 semaphorins, most semaphorins bind directly to plexins, 34 but subclass-specific signaling for semaphorin/plexin has been reported.…”