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PubMed1998

A vacuolar v-t-SNARE complex, the predominant form in vivo and on isolated vacuoles, is disassembled and activated for docking and fusion.

Homotypic vacuole fusion in yeast requires Sec18p (N-ethylmaleimide-sensitive fusion protein [NSF]), Sec17p (soluble NSF attachment protein [alpha-SNAP]), and typical vesicle (v) and target membrane (t) SNAP receptors (SNAREs). We now report that vacuolar v- and t-SNAREs are mainly found with Sec17p as v-t-SNARE complexes in vivo and on purified vacuoles rather than only transiently forming such complexes during docking, and disrupting them upon fusion. In the priming reaction, Sec18p and ATP dissociate this v-t-SNARE complex, accompanied by the release of Sec17p. SNARE complex structure governs each functional aspect of priming, as the v-SNARE regulates the rate of Sec17p release and, in turn, Sec17p-dependent SNARE complex disassembly is required for independent function of the two SNAREs. Sec17p physically and functionally interacts largely with the t-SNARE. (a) Antibodies to the t-SNARE, but not the v-SNARE, block Sec17p release. (b) Sec17p is associated with the t-SNARE in the absence of v-SNARE, but is not bound to the v-SNARE without t-SNARE. (c) Vacuoles with t-SNARE but no v-SNARE still require Sec17p/Sec18p priming, whereas their fusion partners with v-SNARE but no t-SNARE do not. Sec18p thus acts, upon ATP hydrolysis, to disassemble the v-t-SNARE complex, prime the t-SNARE, and release the Sec17p to allow SNARE participation in docking and fusion. These studies suggest that the analogous ATP-dependent disassembly of the 20-S complex of NSF, alpha-SNAP, and v- and t-SNAREs, which has been studied in detergent extracts, corresponds to the priming of SNAREs for docking rather than to the fusion of docked membranes.

Adenosine Triphosphatases↗
PubMed1998

A role for giantin in docking COPI vesicles to Golgi membranes.

We have previously shown that p115, a vesicle docking protein, binds to two proteins (p130 and p400) in detergent extracts of Golgi membranes. p130 was identified as GM130, a Golgi matrix protein, and was shown to act as a membrane receptor for p115. p400 has now been identified as giantin, a Golgi membrane protein with most of its mass projecting into the cytoplasm. Giantin is found on COPI vesicles and pretreatment with antibodies inhibits both the binding of p115 and the docking of these vesicles with Golgi membranes. In contrast, GM130 is depleted from COPI vesicles and inhibition of the GM130 on Golgi membranes, using either antibodies or an NH2-terminal GM130 peptide, inhibits p115 binding and vesicle docking. Together these results suggest that COPI vesicles are docked by giantin on the COPI vesicles and GM130 on Golgi membranes with p115 providing a bridge.

Animals↗
PubMed2002

A combinatorial approach to protein docking with flexible side chains.

Rigid-body docking approaches are not sufficient to predict the structure of a protein complex from the unbound (native) structures of the two proteins. Accounting for side chain flexibility is an important step towards fully flexible protein docking. This work describes an approach that allows conformational flexibility for the side chains while keeping the protein backbone rigid. Starting from candidates created by a rigid-docking algorithm, we demangle the side chains of the docking site, thus creating reasonable approximations of the true complex structure. These structures are ranked with respect to the binding free energy. We present two new techniques for side chain demangling. Both approaches are based on a discrete representation of the side chain conformational space by the use of a rotamer library. This leads to a combinatorial optimization problem. For the solution of this problem, we propose a fast heuristic approach and an exact, albeit slower, method that uses branch-and-cut techniques. As a test set, we use the unbound structures of three proteases and the corresponding protein inhibitors. For each of the examples, the highest-ranking conformation produced was a good approximation of the true complex structure.

Algorithms↗
PubMed2000

Sequential action of two GTPases to promote vacuole docking and fusion.

Homotypic vacuole fusion occurs by sequential priming, docking and fusion reactions. Priming frees the HOPS complex (Vps 11, 16, 18, 33, 39 and 41) to activate Ypt7p for docking. Here we explore the roles of the GDP and GTP states of Ypt7p using Gdi1p (which extracts Ypt7:GDP), Gyp7p (a GTPase-activating protein for Ypt7p:GTP), GTPgammaS or GppNHp (non-hydrolyzable nucleotides), and mutant forms of Ypt7p that favor either GTP or GDP states. GDP-bound Ypt7p on isolated vacuoles can be extracted by Gdi1p, although only the GTP-bound state allows docking. Ypt7p is converted to the GTP-bound state after priming and stably associates with HOPS. Gyp7p can cause Ypt7p to hydrolyze bound GTP to GDP, driving HOPS release and accelerating Gdi1p-mediated release of Ypt7p. Ypt7p extraction does not inhibit the Ca(2+)-triggered cascade that leads to fusion. However, in the absence of Ypt7p, fusion is still sensitive to GTPgammaS and GppNHp, indicating that there is a second specific GTPase that regulates the calcium flux and hence fusion. Thus, two GTPases sequentially govern vacuole docking and fusion.

Calcium↗
PubMed2001

Rho1p and Cdc42p act after Ypt7p to regulate vacuole docking.

Rho GTPases, which control polarized cell growth through cytoskeletal reorganization, have recently been implicated in the control of endo- and exocytosis. We now report that both Rho1p and Cdc42p have a direct role in mediating the docking stage of homotypic vacuole fusion. Vacuoles prepared from strains with temperature-sensitive alleles of either Rho1p or Cdc42p are thermolabile for fusion. RhoGDI (Rdi1p), which extracts Rho1p and Cdc42p from the vacuole membrane, blocks vacuole fusion. The Rho GTPases can not fulfill their function as long as priming and Ypt7p-dependent tethering are inhibited. However, reactions that are reversibly blocked after docking by the calcium chelator BAPTA have passed the point of sensitivity to Rdi1p. Extraction and removal of Ypt7p, Rho1p and Cdc42p from docked vacuoles (by Gdi1p, Gyp7p and Rdi1p) does not impede subsequent membrane fusion, which is still sensitive to GTPgammaS. Thus, multiple GTPases act in a defined sequence to regulate the docking steps of vacuole fusion.

Alleles↗
PubMed2005

Molecular flexibility in ab initio drug docking to DNA: binding-site and binding-mode transitions in all-atom Monte Carlo simulations.

The dynamics of biological processes depend on the structure and flexibility of the interacting molecules. In particular, the conformational diversity of DNA allows for large deformations upon binding. Drug-DNA interactions are of high pharmaceutical interest since the mode of action of anticancer, antiviral, antibacterial and other drugs is directly associated with their binding to DNA. A reliable prediction of drug-DNA binding at the atomic level by molecular docking methods provides the basis for the design of new drug compounds. Here, we propose a novel Monte Carlo (MC) algorithm for drug-DNA docking that accounts for the molecular flexibility of both constituents and samples the docking geometry without any prior binding-site selection. The binding of the antimalarial drug methylene blue at the DNA minor groove with a preference of binding to AT-rich over GC-rich base sequences is obtained in MC simulations in accordance with experimental data. In addition, the transition between two drug-DNA-binding modes, intercalation and minor-groove binding, has been achieved in dependence on the DNA base sequence. The reliable ab initio prediction of drug-DNA binding achieved by our new MC docking algorithm is an important step towards a realistic description of the structure and dynamics of molecular recognition in biological systems.

Algorithms↗
PubMed2003

In situ activation pattern of Met docking site following renal injury and hypertrophy.

BACKGROUND: Hepatocyte growth factor/scatter factor (HGF/SF) binds to its tyrosine kinase receptor, Met, thereby stimulating diverse cellular responses. The multifunctional docking site in the C-terminal domain mediates the signal of phosphorylated Met receptors to multiple transducers. The tyrosine at position 1356 of the Met docking site is crucial for cell motility and morphogenesis. METHODS: We examined the in situ distribution patterns of the Tyr1356-phosphorylated form of Met with a novel monoclonal antibody following renal injury and renal hypertrophy in rats. Sections of the kidney following either sham operation, transient ischaemia of one kidney or unilateral nephrectomy were analysed using indirect immunofluorescence staining and confocal laser scanning microscopy analysis of total Met protein levels and Tyr1356-phosphorylated Met (Met and pMet, respectively). RESULTS: At 6 h post-treatment, pMet increases in ischaemic kidneys compared with sham-operated kidneys, and these changes become substantial after 48 h in both medulla and cortex of ischaemic kidneys (P < 0.001). We also show significant up-regulation of Met predominantly in the medulla of ischaemic kidneys, 48 h following injury (P < 0.009). Inter-estingly, the stimulus for hypertrophy in the remnant kidney after uninephrectomy and the contra-lateral kidney during ischaemia is not accom-panied by significant up-regulation of Met or pMet staining compared with sham operation at both time points. CONCLUSIONS: We demonstrate in this work, for the first time, in situ detection of tyrosine kinase growth factor receptor docking site activation during pathological processes in the kidney. Using this methodology, we show a significant increase in Met docking site activity in both renal medulla and cortex solely following stimulation by ischaemia and repair.

Animals↗
PubMed1999

Automated docking of peptides and proteins by using a genetic algorithm combined with a tabu search.

A genetic algorithm (GA) combined with a tabu search (TA) has been applied as a minimization method to rake the appropriate associated sites for some biomolecular systems. In our docking procedure, surface complementarity and energetic complementarity of a ligand with its receptor have been considered separately in a two-stage docking method. The first stage was to find a set of potential associated sites mainly based on surface complementarity using a genetic algorithm combined with a tabu search. This step corresponds with the process of finding the potential binding sites where pharmacophores will bind. In the second stage, several hundreds of GA minimization steps were performed for each associated site derived from the first stage mainly based on the energetic complementarity. After calculations for both of the two stages, we can offer several solutions of associated sites for every complex. In this paper, seven biomolecular systems, including five bound complexes and two unbound complexes, were chosen from the Protein Data Bank (PDB) to test our method. The calculated results were very encouraging-the hybrid minimization algorithm successfully reaches the correct solutions near the best binded modes for these protein complexes. The docking results not only predict the bound complexes very well, but also get a relatively accurate complexed conformation for unbound systems. For the five bound complexes, the results show that surface complementarity is enough to find the precise binding modes, the top solution from the tabu list generally corresponds to the correct binding mode. For the two unbound complexes, due to the conformational changes upon binding, it seems more difficult to get their correct binding conformations. The predicted results show that the correct binding mode also corresponds to a relatively large surface complementarity score. In these two test cases, the correct solution can be found in the top several solutions from the tabu list. For unbound complexes, the interaction energy from energetic complementarity is very important, it can be used to filter these solutions from the surface complementarity. After the evaluation of the energetic complementarity, the conformations and orientations close to the crystallographically determined structures are resolved. In most cases, the smallest root mean square distance (r.m.s.d.) from the GA combined with TA solutions is in a relatively small region. Our program of automatic docking is really a universal one among the procedures used for the theoretical study of molecular recognition.

Algorithms↗
PubMed1995

Protein docking for low-resolution structures.

A typical problem for a docking procedure is how to match two molecules with known 3-D structure so as to predict the configuration of their complex. A very serious obstacle to docking is an inherent inaccuracy in the 3-D structures of the molecules. In general, existing molecular recognition techniques are not designed for cases where (i) conformational changes upon macromolecular complex formation are substantial or (ii) the X-ray data on one or both (macro) molecules are not available, and the structures, based on alternative sources (NMR, modeling), are not well defined. We designed a direct computer experiment using molecules totally deprived of any structural features smaller than 7 A. This was performed on the basis of a previously developed docking algorithm. The modified procedure was applied to a number of known protein complexes taken from the Brookhaven Protein Data Bank. In most cases, a pronounced trend towards the correct structure of the molecular complex was clearly indicated and the real binding sites were predicted. The distinction between the prediction of the antigen-antibody complex and other molecular pairs may reflect important differences in the principles of complex formation. The results strongly suggest the use of our recognition procedure for docking studies where the detailed structures of the molecules are lacking.

Algorithms↗
PubMed2004

A novel method for scoring of docked protein complexes using predicted protein-protein binding sites.

Docking algorithms produce many possible structures of a protein-protein complex. In most cases some of them resemble the correct structure within an r.m.s.d. of <3 A. A major challenge in the field of docking is to extract the correct structure out of this pool, the so-called 'scoring'. Here, we introduce a new scoring function, which discriminates between the many wrong and few true conformations. The scoring function is based on measuring the tightness of fit of the two docked proteins at a predicted binding interface. The location of the binding interface is identified using the recently developed computer algorithm ProMate. The new scoring function does not rely on energy considerations. It is therefore tolerant to low-resolution descriptions of the interface. A linear relation between the score and the r.m.s.d. relative to the 'true structure' is found in most of the cases evaluated. The function was tested on the docking results of 21 complexes in their unbound form. It was found to be successful in 77% of the examined cases, defining success as scoring a 'true' result with a p value of better than 0.1.

Algorithms↗
PubMed2002

Docking of protein models.

An adequate description of entire genomes has to include information on the three-dimensional (3D) structure of proteins. Most of these protein structures will be determined by high-throughput modeling procedures. Thus, a structure-based analysis of the network of protein-protein interactions in genomes requires docking methodologies that are capable of dealing with significant structural inaccuracies in the modeled structures of proteins. We present a systematic study of the applicability of our low-resolution docking method to protein models of different accuracies. A representative nonredundant set of 475 cocrystallized protein-protein complexes was used to build an array of models of each protein in the set. A sophisticated procedure was created to generate the models with RMS deviations of 1, 2, 3,., 10 A from the crystal structure. The docking was performed for all the models, and the predictions were compared with the configurations of the original cocrystallized complexes. Statistical analysis showed that the low-resolution docking can determine the gross structural features of protein-protein interactions for a significant percent of complexes of highly inaccurate protein models. Such predictions may serve as starting points for a more detailed structural analysis, as well as complement experimental and computational data on protein-protein interactions obtained by other techniques.

Algorithms↗
PubMed2000

Structure-based thermodynamic analysis of the dissociation of protein phosphatase-1 catalytic subunit and microcystin-LR docked complexes.

The relationship between the structure of a free ligand in solution and the structure of its bound form in a complex is of great importance to the understanding of the energetics and mechanism of molecular recognition and complex formation. In this study, we use a structure-based thermodynamic approach to study the dissociation of the complex between the toxin microcystin-LR (MLR) and the catalytic domain of protein phosphatase-1 (PP-1c) for which the crystal structure of the complex is known. We have calculated the thermodynamic parameters (enthalpy, entropy, heat capacity, and free energy) for the dissociation of the complex from its X-ray structure and found the calculated dissociation constant (4.0 x 10(-11)) to be in excellent agreement with the reported inhibitory constant (3.9 x 10(-11)). We have also calculated the thermodynamic parameters for the dissociation of 47 PP-1c:MLR complexes generated by docking an ensemble of NMR solution structures of MLR onto the crystal structure of PP-1c. In general, we observe that the lower the root-mean-square deviation (RMSD) of the docked complex (compared to the X-ray complex) the closer its free energy of dissociation (deltaGd(o)) is to that calculated from the X-ray complex. On the other hand, we note a significant scatter between the deltaGd(o) and the RMSD of the docked complexes. We have identified a group of seven docked complexes with deltaGd(o) values very close to the one calculated from the X-ray complex but with significantly dissimilar structures. The analysis of the corresponding enthalpy and entropy of dissociation shows a compensation effect suggesting that MLR molecules with significant structural variability can bind PP-1c and that substantial conformational flexibility in the PP-1c:MLR complex may exist in solution.

Bacterial Toxins↗
PubMed2006

The polybasic sequence in the C2B domain of rabphilin is required for the vesicle docking step in PC12 cells.

Rabphilin is generally thought to be involved in the regulation of secretory vesicle exocytosis in neurons and neuroendocrine cells, and it has recently been hypothesized that the C2B domain of rabphilin promotes the docking of dense-core vesicles to the plasma membrane through simultaneous interaction with a vesicle protein, Rab3A/27A, and a plasma membrane protein, SNAP-25 (synaptosome-associated protein of 25 kDa). However, the physiological significance of the rabphilin-SNAP-25 interaction in the vesicle-docking step has never been elucidated. In this study we demonstrated by a mutation analysis that the polybasic sequence (587 KKAKHKTQIKKK 598) in the C2B domain of rabphilin is required for SNAP-25 binding, and that the Asp residues in the Ca(2+)-binding loop 3 (D628 and D630) of the C2B domain are not required. We also investigated the effect of Lys-->Gln (KQ) mutations in the polybasic sequence of the C2B domain on vesicle dynamics by total internal reflection fluorescence microscopy in individual PC12 cells. A rabphilin(KQ) mutant that completely lacks SNAP-25-binding activity significantly decreased the number of plasma-membrane-docked vesicles and strongly inhibited high-KCl-induced dense-core vesicle exocytosis. These results indicate that the polybasic sequence in the C2B domain functions as an effector domain for SNAP-25 and controls the number of 'releasable' vesicles docked to the plasma membrane.

Adaptor Proteins, Signal Transducing↗
PubMed1988

Stress responses in lambs docked and castrated surgically or by the application of rubber rings.

A comparative study has been made in lambs 3 to 6 weeks of age of the behavioural responses and changes in plasma immunoreactive beta-endorphin (ir beta-endorphin) and cortisol after docking or docking plus castration by the application of rubber rings or by surgery. The use of rubber rings on lambs at this age was characterised by very agitated behaviour indicative of considerable distress for a period of up to 1 h. In contrast, surgery was accompanied by some post-operative shock exhibited by reduced exploratory and social behaviour, at least in the lambs exposed to docking plus castration. In the latter group there were highly significant increases in both plasma ir beta-endorphin and cortisol concentrations that may be consistent with the induction of stress-induced analgesia. We conclude that surgery caused less distress than the rubber rings, and is therefore preferable for docking and castration of lambs 3 to 6 weeks of age.

Animals↗
PubMed2003

Tail docking in dogs: a review of the issues.

Different groups in our community hold strong views about tail docking in domestic dogs. These range from veterinary associations and welfare organisations, which typically want the practice banned, to purebred dog associations, which vigorously oppose the introduction of antidocking legislation. An evaluation of the tail docking issue, which is informed and nonemotive, requires the integration of moral views with biological and behavioural facts. In recent years, much data have been accumulated concerning the welfare implications of tail docking. Unfortunately, however, there has been limited transfer of this knowledge to people interested in the issue. In this review some of the main arguments for and against canine tail docking are presented and evaluated.

Amputation, Surgical↗
PubMed2003

Tail docking in dogs: can attitude change be achieved?

The debate about tail docking in domestic dogs continues to rage in many developed countries and attitudes expressed by different community groups remain diametrically opposed. Veterinary associations and welfare organisations typically want the practice banned, while many breeders and pure-bred dog associations just as vigorously oppose the introduction of anti-docking legislation. In recent years, much data have been accumulated concerning the welfare implications of tail docking. A recent evaluation of this literature suggests that the practice has little to recommend it and that, in the absence of reasonable case-by-case justification, it may constitute an unacceptable abuse of a sentient species. Given this situation, it is difficult to understand why many canine interest groups, presumably representing those people who care most about the welfare of companion dogs, should continue to hold such strong attitudes in favour of tail docking. In this review we attempt to explain why different community groups might espouse strong but opposing attitudes, despite having access to the same information. We argue that the theory of cognitive dissonance, popular among social psychologists, may provide a useful framework within which to understand, and attempt to alter, attitudes that persist even though they appear contrary to available empirical evidence.

Animal Welfare↗
PubMed2004

Evidence that fast exocytosis can be predominantly mediated by vesicles not docked at active zones in frog saccular hair cells.

The prevailing model of neurotransmitter release stipulates that Ca2+ influx triggers the rapid fusion of vesicles that are docked at presynaptic active zones. Under this model, slower tonic release is supported by vesicles clustered nearby that have to translocate to the release sites before fusion. We have examined this hypothesis at the afferent synapse of saccular hair cells of the leopard frog, Rana pipiens. Detailed morphological measurements at this ribbon synapse show that on average 32 vesicles are docked at each active zone. We show that at this 'graded' synapse, depolarization produces an exocytotic 'burst' that is largely complete within 20 ms after fusion of 280 vesicles per active zone, almost an order of magnitude more than expected. Recovery from paired pulse depression occurs with a time constant of 29 ms, indicating that replenishment of this fast-fusing pool of vesicles is also fast. Our results suggest that non-docked vesicles are capable of fast fusion and that these vesicles constitute the vast majority of the fast-fusing pool. The view that the population of fast-fusing presynaptic vesicles is limited to docked vesicles therefore requires re-evaluation. We propose that compound fusion, i.e. the fusion of vesicles with each other before and/or after they fuse with the membrane can explain multivesicular release at this synapse.

Animals↗
PubMed2006

Residue conservation information for generating near-native structures in protein-protein docking.

MOTIVATION: Protein-protein docking algorithms typically generate large numbers of possible complex structures with only a few of them resembling the native structure. Recently (Duan et al., Protein Sci, 14:316-218, 2005), it was observed that the surface density of conserved residue positions is high at the interface regions of interacting protein surfaces, except for antibody-antigen complexes, where a lesser number of conserved positions than average is observed at the interface regions. Using this observation, we identified putative interacting regions on the surface of interacting partners and significantly improved docking results by assigning top ranks to near-native complex structures. In this paper, we combine the residue conservation information with a widely used shape complementarity algorithm to generate candidate complex structures with a higher percentage of near-native structures (hits). What is new in this work is that the conservation information is used early in the generation stage and not only in the ranking stage of the docking algorithm. This results in a significantly larger number of generated hits and an improved predictive ability in identifying the native structure of protein-protein complexes. RESULTS: We report on results from 48 well-characterized protein complexes, which have enough residue conservation information from the same 59 benchmark complexes used in our previous work. We compute conservation indices of residue positions on the surfaces of interacting proteins using available homologous sequences from UNIPROT and calculate the solvent accessible surface area. We combine this information with shape-complementarity scores to generate candidate protein-protein complex structures. When compared with pure shape-complementarity algorithms, performed by FTDock, our method results in significantly more hits, with the improvement being over 100% in many instances. We demonstrate that residue conservation information is useful not only in refinement and scoring of docking solutions, but also helpful in enrichment of near-native-structures during the generation of candidate geometries of complex structures.

Amino Acid Sequence↗