Genomes and Genes
Experts and Doctors on protein binding in Dortmund, North Rhine Westphalia, Germany
Locale: Dortmund, North Rhine Westphalia, Germany
Topic: protein binding
- Bier D, Rose R, Bravo Rodriguez K, Bartel M, Ramírez Anguita J, Dutt S, et al. Molecular tweezers modulate 14-3-3 protein-protein interactions. Nat Chem. 2013;5:234-9 pubmed publisher..A combination of structural analysis and computer simulations provides rules for the tweezers' binding preferences, thus allowing us to predict their influence on this type of protein-protein interactions. ..
- Rudolph M, Wittinghofer A, Vetter I. Nucleotide binding to the G12V-mutant of Cdc42 investigated by X-ray diffraction and fluorescence spectroscopy: two different nucleotide states in one crystal. Protein Sci. 1999;8:778-87 pubmed..The C-terminus containing the CaaX-motif is partly ordered in both molecules due to an intramolecular disulfide bond formed between Cys105/Cys188 and Cys305/Cys388, respectively. ..
- Rose R, Weyand M, Lammers M, Ishizaki T, Ahmadian M, Wittinghofer A. Structural and mechanistic insights into the interaction between Rho and mammalian Dia. Nature. 2005;435:513-8 pubmed..On the basis of our results, we propose a structural model for the regulation of mDia1 by Rho and DAD. ..
- Breuer S, Schievink S, Schulte A, Blankenfeldt W, Fackler O, Geyer M. Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef. PLoS ONE. 2011;6:e20033 pubmed publisher..Structure determination of the Nef-inhibitor complex reveals the molecular basis for binding specificity. These results establish Nef-NI interfaces as promising leads for the development of potent Nef inhibitors. ..
- Rehmann H, Prakash B, Wolf E, Rueppel A, de Rooij J, Bos J, et al. Structure and regulation of the cAMP-binding domains of Epac2. Nat Struct Biol. 2003;10:26-32 pubmed..We identify a hinge region that couples cAMP binding to a conformational change of the C-terminal regions. Mutations in the hinge of Epac can uncouple cAMP binding from its exchange activity. ..
- Zent E, Vetter I, Wittinghofer A. Structural and biochemical properties of Sept7, a unique septin required for filament formation. Biol Chem. 2011;392:791-7 pubmed publisher..The structure and biochemistry of Sept7 provide new insights into the dynamics of the G interface and outline the differences in the properties of Sept7 compared to the members of group 2 septins. ..
- Schlee S, Groemping Y, Herde P, Seidel R, Reinstein J. The chaperone function of ClpB from Thermus thermophilus depends on allosteric interactions of its two ATP-binding sites. J Mol Biol. 2001;306:889-99 pubmed
- Dvorsky R, Blumenstein L, Vetter I, Ahmadian M. Structural insights into the interaction of ROCKI with the switch regions of RhoA. J Biol Chem. 2004;279:7098-104 pubmed..The identified ROCK-binding site of RhoA strikingly supports the assumption of a common consensus-binding site for effector recognition. ..
- Chandra A, Grecco H, Pisupati V, Perera D, Cassidy L, Skoulidis F, et al. The GDI-like solubilizing factor PDE? sustains the spatial organization and signalling of Ras family proteins. Nat Cell Biol. 2011;14:148-58 pubmed publisher..Our findings link the activity of PDE? in determining Ras protein topography to Ras-dependent signalling. ..
- Ghosh A, Praefcke G, Renault L, Wittinghofer A, Herrmann C. How guanylate-binding proteins achieve assembly-stimulated processive cleavage of GTP to GMP. Nature. 2006;440:101-4 pubmed
- Esser D, Bauer B, Wolthuis R, Wittinghofer A, Cool R, Bayer P. Structure determination of the Ras-binding domain of the Ral-specific guanine nucleotide exchange factor Rlf. Biochemistry. 1998;37:13453-62 pubmed..Raf-RBD. However, comparison of the putatively interacting regions revealed structural differences which are proposed to be responsible for the different substrate affinities of Rlf-, RalGDS-, and Raf-RBD. ..
- Vetter I, Nowak C, Nishimoto T, Kuhlmann J, Wittinghofer A. Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport. Nature. 1999;398:39-46 pubmed..Such a mechanism represents a new type of switch mechanism and regulatory protein-protein interaction for a Ras-related protein. ..
- Uhlenbrock K, Weiwad M, Wetzker R, Fischer G, Wittinghofer A, Rubio I. Reassessment of the role of FKBP38 in the Rheb/mTORC1 pathway. FEBS Lett. 2009;583:965-70 pubmed publisher..Cell biological experiments illustrate that FKBP38 plays only a very minor, if any, role in mTORC1 activation. Our data document that FKBP38 is not the long-sought Rheb effector linking Rheb to mTORC1 activation. ..
- Schumacher B, Mondry J, Thiel P, Weyand M, Ottmann C. Structure of the p53 C-terminus bound to 14-3-3: implications for stabilization of the p53 tetramer. FEBS Lett. 2010;584:1443-8 pubmed publisher..The structure exhibits a potential binding site for small molecules that could stabilize the p53/14-3-3 protein complex suggesting the possibility for therapeutic intervention. ..
- Gasper R, Scrima A, Wittinghofer A. Structural insights into HypB, a GTP-binding protein that regulates metal binding. J Biol Chem. 2006;281:27492-502 pubmed publisher..The homology with NifH, the Fe protein subunit of nitrogenase, suggests a mechanistic model for the switch-dependent incorporation of a metal ion into hydrogenases...
- Scrima A, Wittinghofer A. Dimerisation-dependent GTPase reaction of MnmE: how potassium acts as GTPase-activating element. EMBO J. 2006;25:2940-51 pubmed..We propose a model for the juxtaposition of G-domains in the full-length protein and how it induces conformational changes in the putative tRNA-modification centre. ..
- Itzen A, Pylypenko O, Goody R, Alexandrov K, Rak A. Nucleotide exchange via local protein unfolding--structure of Rab8 in complex with MSS4. EMBO J. 2006;25:1445-55 pubmed..Coupling of nucleotide exchange activity to a cycle of GTPase unfolding and refolding represents a novel nucleotide exchange mechanism. ..
- Alexandrov K, Simon I, Yurchenko V, Iakovenko A, Rostkova E, Scheidig A, et al. Characterization of the ternary complex between Rab7, REP-1 and Rab geranylgeranyl transferase. Eur J Biochem. 1999;265:160-70 pubmed..Based on these experiments, we propose that RabGGTase recognizes the overall structure arising from the association of Rab and REP and then 'scans' the flexible C-terminus to position the proximal cysteines into the active site. ..
- Bergbrede T, Pylypenko O, Rak A, Alexandrov K. Structure of the extremely slow GTPase Rab6A in the GTP bound form at 1.8A resolution. J Struct Biol. 2005;152:235-8 pubmed..82A resolution. Analysis of the structure suggests that low catalytic activity of the Rab6A might be due to high flexibility of the Switch II region and a low degree of constraint of critically important for catalysis Gln 72. ..
- Harjes S, Bayer P, Scheidig A. The crystal structure of human PAPS synthetase 1 reveals asymmetry in substrate binding. J Mol Biol. 2005;347:623-35 pubmed..These observations strongly indicate structural changes during the reaction cycle. Furthermore crystals soaked with ADP and APS could be prepared and the corresponding structures could be solved. ..
- Itzen A, Goody R. GTPases involved in vesicular trafficking: structures and mechanisms. Semin Cell Dev Biol. 2011;22:48-56 pubmed publisher..The basic structural and mechanistic properties of these proteins and their interactions with partner proteins and membranes are reviewed and compared in this article...
- Oesterlin L, Goody R, Itzen A. Posttranslational modifications of Rab proteins cause effective displacement of GDP dissociation inhibitor. Proc Natl Acad Sci U S A. 2012;109:5621-6 pubmed publisher..We therefore speculate that human cells could employ similar mechanisms in the absence of infection to effectively displace Rabs from GDI...
- Czudnochowski N, Bösken C, Geyer M. Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition. Nat Commun. 2012;3:842 pubmed publisher..HIV-1 Tat/TAR abrogates Hexim1 inhibition to stimulate transcription of viral genes but does not change the substrate specificity. Together, these results provide insight into the multifaceted pattern of CTD phosphorylation. ..
- Molzan M, Ottmann C. Synergistic binding of the phosphorylated S233- and S259-binding sites of C-RAF to one 14-3-3? dimer. J Mol Biol. 2012;423:486-95 pubmed publisher..Cellular localization studies validate the significance of these sites for cytoplasmic retention of C-RAF, suggesting an extended mechanism of RAF regulation by 14-3-3 proteins. ..
- Kiel C, Filchtinski D, Spoerner M, Schreiber G, Kalbitzer H, Herrmann C. Improved binding of raf to Ras.GDP is correlated with biological activity. J Biol Chem. 2009;284:31893-902 pubmed publisher..In a luciferase-based reporter gene assay, Raf A85K is associated with higher signaling activity, which appears to be a mere matter of Ras-Raf affinity. ..
- Walter N, Wentsch H, Bührmann M, Bauer S, Döring E, Mayer Wrangowski S, et al. Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38? MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine. J Med Chem. 2017;60:8027-8054 pubmed publisher..Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives. ..
- Mucha E, Hoefle C, Hückelhoven R, Berken A. RIP3 and AtKinesin-13A - a novel interaction linking Rho proteins of plants to microtubules. Eur J Cell Biol. 2010;89:906-16 pubmed publisher..We show that RIP3 is localized at microtubules and interacts with the kinesin-13 family member AtKinesin-13A, suggesting a role for RIP3 in microtubule reorganization and a possible function in ROP-regulated polar growth. ..
- Meyer S, Scrima A, Vers es W, Wittinghofer A. Crystal structures of the conserved tRNA-modifying enzyme GidA: implications for its interaction with MnmE and substrate. J Mol Biol. 2008;380:532-47 pubmed publisher..We propose a model for the interaction between GidA and MnmE, which is supported by site-directed mutagenesis. Our data suggest that this interaction is modulated and potentially regulated by the switch function of the G domain of MnmE...
- Würtele M, Wolf E, Pederson K, Buchwald G, Ahmadian M, Barbieri J, et al. How the Pseudomonas aeruginosa ExoS toxin downregulates Rac. Nat Struct Biol. 2001;8:23-6 pubmed..Considering the intrinsic resistance of P. aeruginosa to antibiotics, this might open up a new avenue towards blocking its pathogenicity. ..
- Quentmeier A, Hellwig P, Bardischewsky F, Grelle G, Kraft R, Friedrich C. Sulfur oxidation in Paracoccus pantotrophus: interaction of the sulfur-binding protein SoxYZ with the dimanganese SoxB protein. Biochem Biophys Res Commun. 2003;312:1011-8 pubmed..This reaction depended on time and the SoxB concentration, and demonstrated the interaction of these two Sox proteins...
- Hanzal Bayer M, Linari M, Wittinghofer A. Properties of the interaction of Arf-like protein 2 with PDEdelta. J Mol Biol. 2005;350:1074-82 pubmed..Among all Arl proteins tested, PDEdelta only interacted with the closely related proteins Arl2 and Arl3, strongly suggesting that Arl2/3 are specific regulators of PDEdelta. ..
- Hillig R, Renault L, Vetter I, Drell T, Wittinghofer A, Becker J. The crystal structure of rna1p: a new fold for a GTPase-activating protein. Mol Cell. 1999;3:781-91 pubmed..Therefore, we suggest a GAP mechanism for rna1p, which constitutes a variation of the arginine finger mechanism found for Ras GAP and RhoGAP. ..
- Thomä N, Niculae A, Goody R, Alexandrov K. Double prenylation by RabGGTase can proceed without dissociation of the mono-prenylated intermediate. J Biol Chem. 2001;276:48631-6 pubmed..It also indicates that the phosphoisoprenoid acts both as a substrate and as a sensor governing the kinetics of protein.protein interactions in the double prenylation reaction. ..
- Harjes S, Scheidig A, Bayer P. Expression, purification and crystallization of human 3'-phosphoadenosine-5'-phosphosulfate synthetase 1. Acta Crystallogr D Biol Crystallogr. 2004;60:350-2 pubmed..The pure protein migrates as a dimer in gel-filtration chromatography. It is moderately active, forming 25 nmol PAPS per minute per milligram. Crystals grow to 100 x 100 x 300 micro m and diffract to 1.75 A. ..
- Rak A, Pylypenko O, Niculae A, Pyatkov K, Goody R, Alexandrov K. Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab prenylation and choroideremia disease. Cell. 2004;117:749-60 pubmed
- Mihai Gazdag E, Streller A, Haneburger I, Hilbi H, Vetter I, Goody R, et al. Mechanism of Rab1b deactivation by the Legionella pneumophila GAP LepB. EMBO Rep. 2013;14:199-205 pubmed publisher..Surprisingly, LepB can function as a GAP for Rab3, Rab8, Rab13 and Rab35, too, suggesting that it has a broader cellular role than previously thought. ..
- Itzen A, Rak A, Goody R. Sec2 is a highly efficient exchange factor for the Rab protein Sec4. J Mol Biol. 2007;365:1359-67 pubmed
- Meyer S, Wittinghofer A, Versées W. G-domain dimerization orchestrates the tRNA wobble modification reaction in the MnmE/GidA complex. J Mol Biol. 2009;392:910-22 pubmed publisher..We finally show that an active GTPase, an intact MnmE/GidA communication, and dimerization of G-domains are necessary for in vivo functioning since mutations disrupting either result in a respiratory deficient phenotype in yeast. ..
- Wätzlich D, Vetter I, Gotthardt K, Miertzschke M, Chen Y, Wittinghofer A, et al. The interplay between RPGR, PDE? and Arl2/3 regulate the ciliary targeting of farnesylated cargo. EMBO Rep. 2013;14:465-72 pubmed publisher..On the basis of these results, we propose a model where RPGR is acting as a scaffold protein recruiting cargo-loaded PDE? and Arl3 to release lipidated cargo into cilia. ..
- Scrima A, Thomas C, Deaconescu D, Wittinghofer A. The Rap-RapGAP complex: GTP hydrolysis without catalytic glutamine and arginine residues. EMBO J. 2008;27:1145-53 pubmed publisher..The structure and biochemical data furthermore show that the RapGAP homologous region of the tumour suppressor Tuberin is sufficient for catalysis on Rheb. ..
- Arens J, Duong T, Dehmelt L. A morphometric screen identifies specific roles for microtubule-regulating genes in neuronal development of P19 stem cells. PLoS ONE. 2013;8:e79796 pubmed publisher..We propose a model that explains how microtubule regulators can mediate cellular morphogenesis during the early steps of neuronal development by controlling microtubule stabilization and organizing dynein-generated forces. ..
- Scheffzek K, Klebe C, Fritz Wolf K, Kabsch W, Wittinghofer A. Crystal structure of the nuclear Ras-related protein Ran in its GDP-bound form. Nature. 1995;374:378-81 pubmed..The amino-terminal (amino-acid residues MAAQGEP) stretch and the acidic tail (DEDDDL) appear to be flexible in the crystal structure. ..
- Brunsveld L, Waldmann H, Huster D. Membrane binding of lipidated Ras peptides and proteins--the structural point of view. Biochim Biophys Acta. 2009;1788:273-88 pubmed publisher..This review will summarize the chemical biology of Ras and discuss in more detail the biophysical and structural features of the membrane bound C-terminus of the protein. ..
- Nassar N, Horn G, Herrmann C, Block C, Janknecht R, Wittinghofer A. Ras/Rap effector specificity determined by charge reversal. Nat Struct Biol. 1996;3:723-9 pubmed..The major determinant for the switch in specificity is the opposite charge of residue 31--Lys in Rap, Glu in Ras--which creates a favourable complementary interface for the Ras-Raf interaction. ..
- Ismail S, Chen Y, Miertzschke M, Vetter I, Koerner C, Wittinghofer A. Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119. EMBO J. 2012;31:4085-94 pubmed publisher..This leads us to propose that ciliary targeting of myristoylated proteins is not only dependent on nucleotide status but also on the cellular localization of Arl3. ..
- Klostermeier D, Seidel R, Reinstein J. The functional cycle and regulation of the Thermus thermophilus DnaK chaperone system. J Mol Biol. 1999;287:511-25 pubmed..DafATth.DnaJTth complex until it is replaced by substrate proteins under heat shock conditions. ..
- Thomä N, Iakovenko A, Kalinin A, Waldmann H, Goody R, Alexandrov K. Allosteric regulation of substrate binding and product release in geranylgeranyltransferase type II. Biochemistry. 2001;40:268-74 pubmed..In summary, these results demonstrate that GGpp acts as an allosteric activator that stabilizes the Rab7:REP-1:GGTase-II complex and triggers product release upon prenylation, preventing product inhibition of the enzyme. ..
- Kulik V, Weyand M, Seidel R, Niks D, Arac D, Dunn M, et al. On the role of alphaThr183 in the allosteric regulation and catalytic mechanism of tryptophan synthase. J Mol Biol. 2002;324:677-90 pubmed..The structural basis for the reduced alpha-activity has its origins in the missing hydrogen bond between alphaThr183 and the catalytic residue, alphaAsp60...
- Rak A, Pylypenko O, Durek T, Watzke A, Kushnir S, Brunsveld L, et al. Structure of Rab GDP-dissociation inhibitor in complex with prenylated YPT1 GTPase. Science. 2003;302:646-50 pubmed..Analysis of the structure provides a molecular basis for understanding a RabGDI mutant that causes mental retardation in humans. ..
- Berken A, Thomas C, Wittinghofer A. A new family of RhoGEFs activates the Rop molecular switch in plants. Nature. 2005;436:1176-80 pubmed..RopGEFs may represent the missing link in signal transduction from receptor kinases to Rops and their identification has implications for the evolution of the Rho molecular switch. ..
- Thomas C, Fricke I, Scrima A, Berken A, Wittinghofer A. Structural evidence for a common intermediate in small G protein-GEF reactions. Mol Cell. 2007;25:141-9 pubmed..The features of the latter complex, a transient intermediate of the exchange reaction never directly observed before, suggest a common mechanism of catalyzed nucleotide exchange applicable to small G proteins in general. ..
- Ignatev A, Kravchenko S, Rak A, Goody R, Pylypenko O. A structural model of the GDP dissociation inhibitor rab membrane extraction mechanism. J Biol Chem. 2008;283:18377-84 pubmed publisher..We suggest a model for the interaction of GDI with prenylated Rab proteins that incorporates a stepwise increase in affinity as the three different partial interactions are successively formed. ..
- Thomä N, Iakovenko A, Goody R, Alexandrov K. Phosphoisoprenoids modulate association of Rab geranylgeranyltransferase with REP-1. J Biol Chem. 2001;276:48637-43 pubmed..Implications of these findings for the role of REP-1 in the prenylation reaction are discussed. ..
- Linnemann T, Kiel C, Herter P, Herrmann C. The activation of RalGDS can be achieved independently of its Ras binding domain. Implications of an activation mechanism in Ras effector specificity and signal distribution. J Biol Chem. 2002;277:7831-7 pubmed..Conversely, the Ras x RalGDS complex has a short lifetime of 0.1 s and Rap1 forms a long-lived complex with RalGDS, possibly explaining its antagonistic effect on Ras. ..
- Blumenstein L, Ahmadian M. Models of the cooperative mechanism for Rho effector recognition: implications for RhoA-mediated effector activation. J Biol Chem. 2004;279:53419-26 pubmed
- Ignatev A, Piatkov K, Pylypenko O, Rak A. A size filtration approach to purify low affinity complexes for crystallization. J Struct Biol. 2007;159:154-7 pubmed..The resulting model of the low affinity unprenylated Rab-GDI complex should reflect a transient Rab-GDI complex when GDI is bound to the membrane-anchored Rab protein and is poised to extract Rab to cytosol. ..
- Liu Y, Petrovic A, Rombaut P, Mosalaganti S, Keller J, Raunser S, et al. Insights from the reconstitution of the divergent outer kinetochore of Drosophila melanogaster. Open Biol. 2016;6:150236 pubmed publisher..Our studies shed light on the structural and functional organization of a highly divergent kinetochore particle. ..
- Friese A, Faesen A, Huis In t Veld P, Fischböck J, Prumbaum D, Petrovic A, et al. Molecular requirements for the inter-subunit interaction and kinetochore recruitment of SKAP and Astrin. Nat Commun. 2016;7:11407 pubmed publisher..Collectively, our studies represent the first thorough mechanistic analysis of SKAP and Astrin, and significantly advance our functional understanding of these important mitotic proteins. ..
- Schulte A, Stolp B, Schönichen A, Pylypenko O, Rak A, Fackler O, et al. The human formin FHOD1 contains a bipartite structure of FH3 and GTPase-binding domains required for activation. Structure. 2008;16:1313-23 pubmed publisher..Mutation of one residue in the predicted DAD-interaction surface efficiently activates FHOD1 in cells. These results demonstrate that DRFs have evolved different molecular solutions to govern their autoregulation and GTPase specificity. ..
- Guo Z, Wu Y, Das D, Delon C, Cramer J, Yu S, et al. Structures of RabGGTase-substrate/product complexes provide insights into the evolution of protein prenylation. EMBO J. 2008;27:2444-56 pubmed publisher..On the basis of our structural and thermodynamic data, we propose that RabGGTase has evolved from a GGTase-I-like molecule that 'learned' to interact with a recycling factor (GDI) that, in turn, eventually gave rise to REP. ..