2dfk Citations

The crystal structure of Cdc42 in complex with collybistin II, a gephyrin-interacting guanine nucleotide exchange factor.

J. Mol. Biol. 359 35-46 (2006)
Cited: 31 times
EuropePMC logo PMID: 16616186


The synaptic localization of ion channel receptors is essential for efficient synaptic transmission and the precise regulation of diverse neuronal functions. In the central nervous system, ion channel receptors reside in the postsynaptic membrane where they are juxtaposed to presynaptic terminals. For proper function, these ion channels have to be anchored to the cytoskeleton, and in the case of the inhibitory glycine and gamma-amino-butyric acid type A (GABA(A)) receptors this interaction is mediated by a gephyrin centered scaffold. Highlighting its central role in this receptor anchoring scaffold, gephyrin interacts with a number of proteins, including the neurospecific guanine nucleotide exchange factor collybistin. Collybistin belongs to the Dbl family of guanine nucleotide exchange factors, occurs in multiple splice variants, and is specific for Cdc42, a small GTPase belonging to the Rho family. The 2.3 Angstroms resolution crystal structure of the Cdc42-collybistin II complex reveals a novel conformation of the switch I region of Cdc42. It also provides the first direct observation of structural changes in the relative orientation of the Dbl-homology domain and the pleckstrin-homology domain in the same Dbl family protein. Biochemical data indicate that gephyrin negatively regulates collybistin activity.

Articles - 2dfk mentioned but not cited (1)

  1. p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. Barrows D, Schoenfeld SM, Hodakoski C, Silkov A, Honig B, Couvillon A, Shymanets A, Nürnberg B, Asara JM, Parsons R. J. Biol. Chem. 290 28915-28931 (2015)

Reviews citing this publication (6)

  1. Gephyrin: a master regulator of neuronal function? Tyagarajan SK, Fritschy JM. Nat. Rev. Neurosci. 15 141-156 (2014)
  2. Shaping inhibition: activity dependent structural plasticity of GABAergic synapses. Flores CE, Méndez P. Front Cell Neurosci 8 327 (2014)
  3. Molecular and functional heterogeneity of GABAergic synapses. Fritschy JM, Panzanelli P, Tyagarajan SK. Cell. Mol. Life Sci. 69 2485-2499 (2012)
  4. Gephyrin: where do we stand, where do we go? Fritschy JM, Harvey RJ, Schwarz G. Trends Neurosci. 31 257-264 (2008)
  5. The genetics of hyperekplexia: more than startle! Harvey RJ, Topf M, Harvey K, Rees MI. Trends Genet. 24 439-447 (2008)
  6. Trafficking and synaptic anchoring of ionotropic inhibitory neurotransmitter receptors. Kneussel M, Loebrich S. Biol. Cell 99 297-309 (2007)

Articles citing this publication (24)

  1. A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. Kalscheuer VM, Musante L, Fang C, Hoffmann K, Fuchs C, Carta E, Deas E, Venkateswarlu K, Menzel C, Ullmann R, Tommerup N, Dalprà L, Tzschach A, Selicorni A, Lüscher B, Ropers HH, Harvey K, Harvey RJ. Hum. Mutat. 30 61-68 (2009)
  2. Complex role of collybistin and gephyrin in GABAA receptor clustering. Saiepour L, Fuchs C, Patrizi A, Sassoè-Pognetto M, Harvey RJ, Harvey K. J. Biol. Chem. 285 29623-29631 (2010)
  3. Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression. Mitin N, Betts L, Yohe ME, Der CJ, Sondek J, Rossman KL. Nat. Struct. Mol. Biol. 14 814-823 (2007)
  4. PH-domain-driven targeting of collybistin but not Cdc42 activation is required for synaptic gephyrin clustering. Reddy-Alla S, Schmitt B, Birkenfeld J, Eulenburg V, Eulenburg V, Dutertre S, Böhringer C, Götz M, Betz H, Papadopoulos T. Eur. J. Neurosci. 31 1173-1184 (2010)
  5. Collybistin splice variants differentially interact with gephyrin and Cdc42 to regulate gephyrin clustering at GABAergic synapses. Tyagarajan SK, Ghosh H, Harvey K, Fritschy JM. J. Cell. Sci. 124 2786-2796 (2011)
  6. Splice-specific glycine receptor binding, folding, and phosphorylation of the scaffolding protein gephyrin. Herweg J, Schwarz G. J. Biol. Chem. 287 12645-12656 (2012)
  7. The DH and PH domains of Trio coordinately engage Rho GTPases for their efficient activation. Chhatriwala MK, Betts L, Worthylake DK, Sondek J. J. Mol. Biol. 368 1307-1320 (2007)
  8. Collybistin is required for both the formation and maintenance of GABAergic postsynapses in the hippocampus. Papadopoulos T, Eulenburg V, Eulenburg V, Reddy-Alla S, Mansuy IM, Li Y, Betz H. Mol. Cell. Neurosci. 39 161-169 (2008)
  9. Asef2 functions as a Cdc42 exchange factor and is stimulated by the release of an autoinhibitory module from a concealed C-terminal activation element. Hamann MJ, Lubking CM, Luchini DN, Billadeau DD. Mol. Cell. Biol. 27 1380-1393 (2007)
  10. Mechanistic insights into specificity, activity, and regulatory elements of the regulator of G-protein signaling (RGS)-containing Rho-specific guanine nucleotide exchange factors (GEFs) p115, PDZ-RhoGEF (PRG), and leukemia-associated RhoGEF (LARG). Jaiswal M, Gremer L, Dvorsky R, Haeusler LC, Cirstea IC, Uhlenbrock K, Ahmadian MR. J. Biol. Chem. 286 18202-18212 (2011)
  11. The role of collybistin in gephyrin clustering at inhibitory synapses: facts and open questions. Papadopoulos T, Soykan T. Front Cell Neurosci 5 11 (2011)
  12. Synaptic plasticity, a symphony in GEF. Kiraly DD, Eipper-Mains JE, Mains RE, Eipper BA. ACS Chem Neurosci 1 348-365 (2010)
  13. Differential regulation of the postsynaptic clustering of γ-aminobutyric acid type A (GABAA) receptors by collybistin isoforms. Chiou TT, Bonhomme B, Jin H, Miralles CP, Xiao H, Fu Z, Harvey RJ, Harvey K, Vicini S, De Blas AL. J. Biol. Chem. 286 22456-22468 (2011)
  14. A conformational switch in collybistin determines the differentiation of inhibitory postsynapses. Soykan T, Schneeberger D, Tria G, Buechner C, Bader N, Svergun D, Tessmer I, Poulopoulos A, Papadopoulos T, Varoqueaux F, Schindelin H, Brose N. EMBO J. 33 2113-2133 (2014)
  15. Galpha q allosterically activates and relieves autoinhibition of p63RhoGEF. Shankaranarayanan A, Boguth CA, Lutz S, Vettel C, Uhlemann F, Aittaleb M, Wieland T, Tesmer JJ. Cell. Signal. 22 1114-1123 (2010)
  16. Collybistin activation by GTP-TC10 enhances postsynaptic gephyrin clustering and hippocampal GABAergic neurotransmission. Mayer S, Kumar R, Jaiswal M, Soykan T, Ahmadian MR, Brose N, Betz H, Rhee JS, Papadopoulos T. Proc. Natl. Acad. Sci. U.S.A. 110 20795-20800 (2013)
  17. The role of the conserved switch II glutamate in guanine nucleotide exchange factor-mediated nucleotide exchange of GTP-binding proteins. Gasper R, Thomas C, Ahmadian MR, Wittinghofer A. J. Mol. Biol. 379 51-63 (2008)
  18. The Phosphatidylinositol (3,4,5)-Trisphosphate-dependent Rac Exchanger 1·Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1·Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells. Lucato CM, Halls ML, Ooms LM, Liu HJ, Mitchell CA, Whisstock JC, Ellisdon AM. J. Biol. Chem. 290 20827-20840 (2015)
  19. Lipid binding defects and perturbed synaptogenic activity of a Collybistin R290H mutant that causes epilepsy and intellectual disability. Papadopoulos T, Schemm R, Grubmüller H, Brose N. J. Biol. Chem. 290 8256-8270 (2015)
  20. Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism. Long P, May MM, James VM, Grannò S, Johnson JP, Tarpey P, Stevenson RE, Harvey K, Schwartz CE, Harvey RJ. Front Mol Neurosci 8 83 (2015)
  21. Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3. Cash JN, Davis EM, Tesmer JJG. Structure 24 730-740 (2016)
  22. Gs and Gq signalings regulate hPEM-2-induced cell responses in Neuro-2a cells. Nagae R, Sato K, Yasui Y, Banno Y, Nagase T, Ueda H. Biochem. Biophys. Res. Commun. 415 168-173 (2011)
  23. Structurally unique interaction of RBD-like and PH domains is crucial for yeast pheromone signaling. Yerko V, Sulea T, Ekiel I, Harcus D, Baardsnes J, Cygler M, Whiteway M, Wu C. Mol. Biol. Cell 24 409-420 (2013)
  24. Receptor tyrosine kinase EphA7 is required for interneuron connectivity at specific subcellular compartments of granule cells. Beuter S, Ardi Z, Horovitz O, Wuchter J, Keller S, Saha R, Tripathi K, Anunu R, Kehat O, Kriebel M, Richter-Levin G, Volkmer H. Sci Rep 6 29710 (2016)