Giles K

General

Full name : Giles Kurt

First name : Kurt

Mail : Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143\; Department of Neurology, University of California, San Francisco, CA 94143

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Country : USA

Email : kurt.giles@ucsf.edu

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References (11)

Title : Hydrophobic protein that copurifies with human brain acetylcholinesterase: amino acid sequence, genomic organization, and chromosomal localization - Navaratnam_2000_J.Neurochem_74_2146
Author(s) : Navaratnam DS , Fernando FS , Priddle JD , Giles K , Clegg SM , Pappin DJ , Craig I , Smith AD
Ref : Journal of Neurochemistry , 74 :2146 , 2000
Abstract : The mechanism of attachment of acetylcholinesterase (AChE) to neuronal membranes in interneuronal synapses is poorly understood. We have isolated, sequenced, and cloned a hydrophobic protein that copurifies with AChE from human caudate nucleus and that we propose forms a part of a complex of membrane proteins attached to this enzyme. It is a short protein of 136 amino acids and has a molecular mass of 18 kDa. The sequence contains stretches of both hydrophobic and hydrophilic amino acids and two cysteine residues. Analysis of the genomic sequence reveals that the coding region is divided among five short exons. Fluorescence in situ hybridization localizes the gene to chromosome 6p21.32-p21.2. Northern blot analysis shows that this gene is widely expressed in the brain with an expression pattern that parallels that of AChE.
ESTHER : Navaratnam_2000_J.Neurochem_74_2146
PubMedSearch : Navaratnam_2000_J.Neurochem_74_2146
PubMedID: 10800960

Title : Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II - Kryger_2000_Acta.Crystallogr.D.Biol.Crystallogr_56_1385
Author(s) : Kryger G , Harel M , Giles K , Toker L , Velan B , Lazar A , Kronman C , Barak D , Ariel N , Shafferman A , Silman I , Sussman JL
Ref : Acta Crystallographica D Biol Crystallogr , 56 :1385 , 2000
Abstract : Structures of recombinant wild-type human acetylcholinesterase and of its E202Q mutant as complexes with fasciculin-II, a 'three-finger' polypeptide toxin purified from the venom of the eastern green mamba (Dendroaspis angusticeps), are reported. The structure of the complex of the wild-type enzyme was solved to 2.8 A resolution by molecular replacement starting from the structure of the complex of Torpedo californica acetylcholinesterase with fasciculin-II and verified by starting from a similar complex with mouse acetylcholinesterase. The overall structure is surprisingly similar to that of the T. californica enzyme with fasciculin-II and, as expected, to that of the mouse acetylcholinesterase complex. The structure of the E202Q mutant complex was refined starting from the corresponding wild-type human acetylcholinesterase structure, using the 2.7 A resolution data set collected. Comparison of the two structures shows that removal of the charged group from the protein core and its substitution by a neutral isosteric moiety does not disrupt the functional architecture of the active centre. One of the elements of this architecture is thought to be a hydrogen-bond network including residues Glu202, Glu450, Tyr133 and two bridging molecules of water, which is conserved in other vertebrate acetylcholinesterases as well as in the human enzyme. The present findings are consistent with the notion that the main role of this network is the proper positioning of the Glu202 carboxylate relative to the catalytic triad, thus defining its functional role in the interaction of acetylcholinesterase with substrates and inhibitors.
ESTHER : Kryger_2000_Acta.Crystallogr.D.Biol.Crystallogr_56_1385
PubMedSearch : Kryger_2000_Acta.Crystallogr.D.Biol.Crystallogr_56_1385
PubMedID: 11053835
Gene_locus related to this paper: human-ACHE

Title : aCHEdb: the database system for ESTHER, the alpha\/beta fold family of proteins and the Cholinesterase gene server - Cousin_1998_Nucleic.Acids.Res_26_226
Author(s) : Cousin X , Hotelier T , Giles K , Toutant JP , Chatonnet A
Ref : Nucleic Acids Research , 26 :226 , 1998
Abstract : Acetylcholinesterase belongs to a family of proteins, the alpha/beta hydrolase fold family, whose constituents evolutionarily diverged from a common ancestor and share a similar structure of a central beta sheet surrounded by alpha helices. These proteins fulfil a wide range of physiological functions (hydrolases, adhesion molecules, hormone precursors) [Krejci,E., Duval,N., Chatonnet,A., Vincens,P. and Massouli,J. (1991) Proc. Natl. Acad. Sci. USA , 88, 6647-6651]. ESTHER (for esterases, alpha/beta hydrolase enzymes and relatives) is a database aimed at collecting in one information system, sequence data together with biological annotations and experimental biochemical results related to the structure-function analysis of the enzymes of the family. The major upgrade of the database comes from the use of a new database management system: aCHEdb which uses the ACeDB program designed by Richard Durbin and Jean Thierry-Mieg. It can be found at http:\/\/http:bioweb.supagro.inra.fr/ESTHER
ESTHER : Cousin_1998_Nucleic.Acids.Res_26_226
PubMedSearch : Cousin_1998_Nucleic.Acids.Res_26_226
PubMedID: 9399841

Title : 3D Structure at 2.7 Resolution of Native and E202Q Mutant Human Acetylcholinesterase Complexed with Fasciculin-II -
Author(s) : Kryger G , Giles K , Harel M , Toker L , Velan B , Lazar A , Kronman C , Barak D , Ariel N , Shafferman A , Silman I , Sussman JL
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :323 , 1998
PubMedID:

Title : 3D Structure of a Complex of Human Acetylcholinesterase with Fasciculin-II at 2.7 Resolution -
Author(s) : Kryger G , Giles K , Harel M , Toker L , Velan B , Lazar A , Kronman C , Barak D , Ariel N , Shafferman A , Silman I , Sussman JL
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :370 , 1998
PubMedID:

Title : Assembly of Acetylcholinesterase Subunits in vitro -
Author(s) : Giles K , Ben-Yohanan R , Velan B , Shafferman A , Sussman JL , Silman I
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :442 , 1998
PubMedID:

Title : Quaternary Structure of Tetrameric Acetylcholinesterase -
Author(s) : Raves ML , Giles K , Schrag JD , Schmid MF , Phillips JN, Jr. , Chiu W , Howard AJ , Silman I , Sussman JL
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :351 , 1998
PubMedID:
Gene_locus related to this paper: eleel-ACHE

Title : Expression and Tissue Distribution of Cholinesterases Via EST Analysis -
Author(s) : Giles K , Silman I , Sussman JL
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :450 , 1998
PubMedID:

Title : Interactions underlying subunit association in cholinesterases - Giles_1997_Protein.Eng_10_677
Author(s) : Giles K
Ref : Protein Engineering , 10 :677 , 1997
Abstract : Cholinesterases occur in a family of molecular forms, both as homo-oligomers of catalytic subunits, which can be either soluble, amphiphilic or lipid-anchored to the membrane; and hetero-oligomers of catalytic subunits and structural subunits. The structural subunits afford a method for precise localization of cholinesterases for specific function. A number of mutagenesis studies suggest that the C-terminal region of one alternatively spliced form of cholinesterase is involved in association of catalytic subunits into tetramers and in the association of these tetramers with structural subunits, however, there is currently no structural information about this region. In addition, none of the mutagenesis studies have clearly defined the residues important in these interactions. Here, multiple sequence alignment, structure prediction techniques and analysis of three-dimensional structural data are combined with a re-examination of mutagenesis and biochemical data. Three-dimensional models for the C-terminal region and for soluble tetrameric cholinesterase are proposed, and a set of rules governing subunit association are formulated. The simple model for association of catalytic and structural subunits presented is consistent with data for all known cholinesterases from species as divergent as nematode and man.
ESTHER : Giles_1997_Protein.Eng_10_677
PubMedSearch : Giles_1997_Protein.Eng_10_677
PubMedID: 9278281

Title : The alpha\/beta hydrolase fold family of proteins database and the cholinesterase gene server ESTHER - Cousin_1997_Nucleic.Acids.Res_25_143
Author(s) : Cousin X , Hotelier T , Giles K , Lievin P , Toutant JP , Chatonnet A
Ref : Nucleic Acids Research , 25 :143 , 1997
Abstract : ESTHER (for esterases, alpha/betahydrolase enzyme and relatives) is a database of sequences phylogenetically related to cholinesterases. These sequences define a homogeneous group of enzymes (carboxylesterases, lipases and hormone-sensitive lipases) sharing a similar structure of a central beta-sheet surrounded by alpha-helices. Among these proteins a wide range of functions can be found (hydrolases, adhesion molecules, hormone precursors). The purpose of ESTHER is to help comparison of structures and functions of members of the family. Since the last release, new features have been added to the server. A BLAST comparison tool allows sequence homology searches within the database sequences. New sections are available: kinetics and inhibitors of cholinesterases, fasciculin-acetylcholinesterase interaction and a gene structure review. The mutation analysis compilation has been improved with three-dimensional images. A mailing list has been created.
ESTHER : Cousin_1997_Nucleic.Acids.Res_25_143
PubMedSearch : Cousin_1997_Nucleic.Acids.Res_25_143
PubMedID: 9016525

Title : Involvement of the NMDA receptor in a non-cholinergic action of acetylcholinesterase in guinea-pig substantia nigra pars compacta neurons - Webb_1996_Eur.J.Neurosci_8_837
Author(s) : Webb CP , Nedergaard S , Giles K , Greenfield SA
Ref : European Journal of Neuroscience , 8 :837 , 1996
Abstract : Evidence is accumulating that a soluble, secretory form of acetylcholinesterase may have novel, non-cholinergic functions in certain brain regions, such as the substantia nigra. In this study, application of human recombinant acetylcholinesterase (rhAChE) to pars compacta neurons in the rostral substantia nigra resulted in a sustained hyperpolarization that was not only mimicked by application of N-methyl-D-aspartate (NMDA) but also blocked by the NMDA receptor antagonists MK8O1 and 2-amino-5-phosphonopentanoic acid. Neither the rhAChE- nor the NMDA-induced hyperpolarization was seen when the calcium chelator BAPTA was injected into the neuron; hence the effect is mediated by accumulation of intracellular calcium. This intracellular calcium appears sufficient to compromise neuronal metabolism since the rhAChE-induced hyperpolarization was reversed by application of the K-ATP channel antagonist tolbutamide. Butyrylcholinesterase, a protein of similar molecular weight to acetylcholinesterase, which also hydrolyses acetylcholine, had no effect whatsoever. The results suggest that, independent of its normal catalytic function, acetylcholinesterase can act via the NMDA receptor complex to enhance calcium entry into nigral neurons and jeopardize cell metabolism. This non-classical action of acetylcholinesterase might thus be an important factor in the mechanisms underlying parkinsonian neurodegeneration.
ESTHER : Webb_1996_Eur.J.Neurosci_8_837
PubMedSearch : Webb_1996_Eur.J.Neurosci_8_837
PubMedID: 9081636