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

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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.

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Acknowledgments

We apologize to investigators whose important work we omitted to cite due to space restraints and want to thank several colleagues and many members of the plexin/sema/neuropilin community. We are especially grateful to John Basile, Alain Chedotal, Jonathan Duke-Cohen, Silvio Gutkind, Michael Klagsbrun, Alex Kolodkin, Fanny Mann, Hee-Won Park, Andreas Püschel, Jakub Swiercz, Junichi Takagi, Luca Tamagnone, Jonathan Terman, Yufeng Tong and Thomas Worzfeld for their comments on parts of this review, as well as to an anonymous reviewer and several members of the Buck lab., particularly Susmita Borthakur and SoonJeung Kim for their help. Taeku Kim assisted with references. This project is supported by NIH Grant GM073071.

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  1. Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH, 44106, USA

    Prasanta K. Hota & Matthias Buck

  2. Department of Neuroscience, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH, 44106, USA

    Matthias Buck

  3. Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH, 44106, USA

    Matthias Buck

  4. Comprehensive Cancer Center, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH, 44106, USA

    Matthias Buck

  5. Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH, 44106, USA

    Matthias Buck

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  1. Prasanta K. Hota
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Correspondence to Matthias Buck.

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Hota, P.K., Buck, M. Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions. Cell. Mol. Life Sci. 69, 3765–3805 (2012). https://doi.org/10.1007/s00018-012-1019-0

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