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PubMed2002

Structure, dynamics and binding characteristics of the second PDZ domain of PTP-BL.

The PDZ domains of the protein tyrosine phosphatase PTP-BL mediate interactions by binding to specific amino acid sequences in target proteins. The solution structure of the second PDZ domain of PTP-BL, PDZ2, displays a compact fold with six beta strands and two alpha-helices. A unique feature of this domain compared to the canonical PDZ fold is an extended flexible loop at the base of the binding pocket, termed L1, that folds back onto the protein backbone, a feature that is shared by both the murine and human orthologues. The structure of PDZ2 differs significantly from the orthologous human structure. A comparison of structural quality indicators clearly demonstrates that the PDZ2 ensemble is statistically more reasonable than that of the human orthologue. The analysis of (15)N relaxation data for PDZ2 shows a normal pattern, with more rigid secondary structures and more flexible loop structures. Close to the binding pocket, Leu85 and Thr88 display greater mobility when compared to surrounding residues. Peptide binding studies demonstrated a lack of interaction between murine PDZ2 and the C terminus of the murine Fas/CD95 receptor, suggesting that the Fas/CD95 receptor is not an in vivo target for PDZ2. In addition, PDZ2 specifically binds the C termini of both human Fas/CD95 receptor and the RIL protein, despite RIL containing a non-canonical PDZ-interacting sequence of E-x-V. A model of PDZ2 with the RIL peptide reveals that the PDZ2 binding pocket is able to accommodate the bulkier side-chain of glutamic acid while maintaining crucial protein to peptide hydrogen bond interactions.

Amino Acid Sequence↗
PubMed2002

Solution structure of protein SRP19 of Archaeoglobus fulgidus signal recognition particle.

Protein SRP19 is an essential RNA-binding component of the signal recognition particle (SRP) in Archaea and Eucarya. A three-dimensional solution structure of the 104 residue SRP19 from the hyperthermophilic archaeon Archaeoglobus fulgidus, designated as Af19, was determined by NMR spectroscopy. Af19 contains three beta-strands, two alpha-helical regions, arranged in a betaalphabetabetaalpha topology, a 3(10) helix, and a disordered C-terminal tail. This fold is similar to the betaalphabetabetaalphabeta RNP motif present in numerous other RNA-binding proteins, which engage their cognate RNAs using conserved sequence motifs present within beta-strands 1 and 3. Mutagenesis studies of human SRP19, however, reveal the major contact sites with SRP RNA reside within loops 1, 3, and 4. These contacts were verified by the crystal structure of human SRP19 complexed to SRP RNA helix 6 reported subsequent to the submission of the manuscript. The crystal structure also reveals that, unlike canonical RNP motifs, SRP19 does not engage specific RNA bases through conserved sequence motifs present within beta-strands 1 and 3. Instead, SRP19 uses residues both within and flanking beta-strand 1 to stabilize the complex through direct and indirect contacts to the phosphate backbone of the tetraloop, leaving the bases of the tetraloop exposed. This, coupled with the fact that SRP19 appears relatively rigid and undergoes only minor changes in structure upon RNA binding, may underlie the molecular basis by which SRP19 functions to initiate SRP assembly.

Amino Acid Sequence↗
PubMed2002

Conformational plasticity in folding of the split beta-alpha-beta protein S6: evidence for burst-phase disruption of the native state.

An increasing number of folding studies of two-state proteins shows that point mutations sometimes change the kinetic m-values, leading to kinks and curves in the chevron plots. The molecular origin of these changes is yet unclear although it is speculated that they are linked to structural rearrangement of the transition state or to accumulation of meta-stable intermediates. To shed more light on this issue, we present here a combined m and phi-value analysis of the split beta-alpha-beta protein S6. Wild-type S6 displays classical two-state kinetics with v-shaped chevron plot, but a majority of its mutants display distinct m-value changes or curved chevrons. We observe that this kinetic aberration of S6 is linked to mutations that are clustered in distinct regions of the native structure. The most pronounced changes, i.e. decrease in the m-value for the unfolding rate constant, are seen upon truncation of interactions between the N and C termini, whereas mutations in the centre of the hydrophobic core show smaller or even opposed effects. As a consequence, the calculated phi-values display a systematic increase upon addition of denaturant. In the case of S6, the phenomenon seems to arise from a general plasticity of the different species on the folding pathway. That is, the structure of the denatured ensemble, the transition state, and the native ground-state for unfolding seem to change upon mutation. From these changes, it is concluded that interactions spanning the centre of the hydrophobic core form early in folding, whereas the entropically disfavoured interactions linking the N and C termini consolidate very late, mainly on the down-hill-side of the folding barrier.

Amino Acid Sequence↗
PubMed2002

Stiffness of the distal loop restricts the structural heterogeneity of the transition state ensemble in SH3 domains.

Protein engineering experiments and Phi(F)-value analysis of SH3 domains reveal that their transition state ensemble (TSE) is conformationally restricted, i.e. the fluctuations in the transition state (TS) structures are small. In the TS of src SH3 and alpha-spectrin SH3 the distal loop and the associated hairpin are fully structured, while the rest of the protein is relatively disordered. If native structure predominantly determines the folding mechanism, the findings for SH3 folds raise the question: What are the features of the native topology that determine the nature of the TSE? We propose that the presence of stiff loops in the native state that connect local structural elements (such as the distal hairpin in SH3 domains) conformationally restricts TSE. We validate this hypothesis using the simulations of a "control" system (16 residue beta-hairpin forming C-terminal fragment of the GBl protein) and its variants. In these fragments the role of bending rigidity in determining the nature of the TSE can be directly examined without complications arising from interactions with the rest of the protein. The TSE structures in the beta-hairpins are determined computationally using cluster analysis and limited Phi(F)-value analysis. Both techniques prove that the conformational heterogeneity decreases as the bending rigidity of the loop increases. To extend this finding to SH3 domains a measure of bending rigidity based on loop curvature, which utilizes native structures in the Protein Data Bank (PDB), is introduced. Using this measure we show that, with few exceptions, the ordering of stiffness of the distal, n-src, and RT loops in the 29 PDB structures of SH3 domains is conserved. Combining the simulation results for beta-hairpins and the analysis of PDB structures for SH3 domains, we propose that the stiff distal loop restricts the conformational fluctuations in the TSE. We also predict that constraining the distal loop to be preformed in the denatured ensemble should not alter the nature of TSE. On the other hand, if the amino and carboxy terminals are cross-linked to form a circular polypeptide chain, the pathways and TSs are altered. These contrasting scenarios are illustrated using simulations of cross-linked WT beta-hairpin fragments. Computations of bending rigidities for immunoglobulin-like domain proteins reveal no clear separation in the stiffness of their loops. In the beta-sandwich proteins, which have large fractions of non-local native contacts, the nature of the TSE cannot be apparently determined using purely local structural characteristics. Nevertheless, the measure of loop stiffness still provides qualitative predictions of the ordered regions in the TSE of Ig27 and TenFn3.

Amino Acid Sequence↗
PubMed2000

A statistical mechanical model for predicting B-DNA curvature and flexibility.

A statistical mechanical model taking into account the symmetric twisting, tilting, sliding fluctuations and asymmetric rolling fluctuations has been proposed to predict the macroscopic curvature and flexibility of B-DNA. Based on the statistical data of structural parameters of double helix in nucleic acid database and the related theoretical analysis, the equilibrium angular parameters (Omega, rho and tau) describing the orientation of successive base-pair planes, the translation parameters (D(y)) along the long axis of neighboring base-pair step and the corresponding force constants are arranged for ten dimers appropriately. Under the assumption of independent angular parameters, independent base-pair steps and a simple energy function, we can calculate the macroscopic curvature and the flexibility of DNA sequences through the transformation matrix and the Boltzmann ensemble average. The predictions on curvature and flexibility of DNA have been compared with the corresponding experimental data. The agreement is remarkably good. It is demonstrated that the lowering of the temperature does increase the DNA curvature.

Animals↗
PubMed2002

Mechanical implications of the domain structure of fiber-forming collagens: comparison of the molecular and fibrillar flexibilities of the alpha1-chains found in types I-III collagen.

Fibrillar collagens store, transmit and dissipate elastic energy during tensile deformation. Results of previous studies suggest that the collagen molecule is made up of alternating rigid and flexible domains, and extension of the flexible domains is associated with elastic energy storage. In this study, we model the flexibility of the alpha1-chains found in types I-III collagen molecules and microfibrils in order to understand the molecular basis of elastic energy storage in collagen fibers by analysing the areas under conformational plots for dipeptide sequences. Results of stereochemical modeling suggest that the collagen triple helix is made up of rigid and flexible domains that alternate with periods that are multiples of three amino acid residues. The relative flexibility of dipeptide sequences found in the flexible regions is about a factor of five higher than that found for the flexibility of the rigid regions, and the flexibility of types II and III collagen molecules appears to be higher than that found for the type I collagen molecule. The different collagen alpha1-chains were compared by correlating the flexibilities. The results suggest that the flexibilities of the alpha1-chains of types I and III collagen are more closely related than the flexibilities of the alpha1-chains in types I and II and II and III collagen. The flexible domains found in the alpha1-chains of types I-III collagen were found to be conserved in the microfibril and had periods of about 15 amino acid residues and multiples thereof. The flexibility profiles of types I and II collagen microfibrils were found to be more highly correlated than those for types I and III and II and III. These results suggest that the domain structure of the alpha1-chains found in types I-III collagen is an efficient means for storage of elastic energy during stretching while preserving the triple helical structure of the overall molecule. It is proposed that all collagens that form fibers are designed to act as storage elements for elastic energy. The function of fibers rich in type I collagen is to store and then transmit this energy while fibers rich in types II and III collagen may store and then reflect elastic energy for dissipation through viscous fibrillar slippage. Impaired elastic energy storage by extracellular matrices may lead to cellular damage and changes in signaling by mechanochemical transduction at the extracellular matrix-cell interface.

Animals↗
PubMed2000

Interaction of the papillomavirus E2 protein with mitotic chromosomes.

The bovine papillomavirus E2 transactivator protein is a multifunctional protein that activates viral transcription, cooperates in initiation of viral DNA replication, and is required for long-term episomal maintenance of viral genomes. We have shown previously that the E2 transactivator protein and bovine papillomavirus type 1 genomes are associated with mitotic chromosomes and have proposed that E2 links the genomes to cellular chromosomes to ensure segregation to daughter nuclei. In this study, we show that E2 is associated with cellular chromosomes at all stages of mitosis. We also further map the regions of E2 that are required for this association. The transactivation domain of E2 is necessary and sufficient to mediate the interaction with mitotic chromosomes; the DNA binding domain, and the flexible hinge region that separates the two domains, is not required. Furthermore, mutation of previously identified phosphorylation sites (serine residues 235, 298, and 301) has no effect on the ability of the E2 protein to bind mitotic chromosomes.

Animals↗
PubMed1996

Bending and torquing accuracy of the bending art system (BAS).

With the bending art system (BAS) the computerized production of individual arch wires has become possible. The BAS consists of an intraoral camera, a computer program and a bending machine producing the archwire by consecutive bending and twisting procedures. This study examines the accuracy of the bending machine when using 0.016" x 0.016" and 0.016" x 0.022" steel wire of rectangular cross-section. Bending angles ranging from 6 degrees to 54 degrees, and torsion angles ranging from 2 degrees to 35 degrees were tested; also the minimum distance between these individual operations was determined. The bent pieces of wire were analysed in a 3D-coordinate gauging system. The 0.016" x 0.016" steel wire showed a mean measuring error of 0.62 degree in bending procedures and of 0.72 degree in torsion procedures, whereas the 0.016" x 0.022" steel wire showed an error of 0.87 degree with edgewise bendings and of 0.86 degree with torsions. To ensure this accuracy a minimum distance of 0.5 mm to 0.7 mm, depending on which kind of bending combination is used, between bending and torsion is required. The error could be reduced even further if a more constant wire material and a more accurate calibration of the bending machine were used. All in all the precision of the bending machine meets the clinical requirements.

Computer-Aided Design↗
PubMed1997

Effect of medication on biomechanical properties of rabbit bones: heparin induced osteoporosis.

The aim of this controlled study is to investigate the effect of heparin on osteoporosis initiation and of calcitonin and tamoxifen on the progress of osteoporosis induced by heparin through biomechanical means and, thus, to assist in clinical usage of these drugs. 32 four-month-old female New Zealand white rabbits were divided into four different experimental groups. The animals in group A were administered heparin (Liquemine) intraperitoneally at the dosage of 1000 IU/kg/day. The animals in group B were injected the same amount of heparin as those of group A, and in addition, were given calcitonin at the dosage of 100 IU/kg/day. The animals in group C were medicated the same way as group B but 2 mg/kg/day tamoxifen (Nolvadex) was orally added into their intestine via cannula, one side connected to the injector. The animals in group D were the control. The experiment lasted 8 weeks. The animals in all experimental groups showed the same growth pattern as that of the control group. Whole-bone femur, humerus and tibia specimens were subjected to 3-point bending tests while sections from the proximal ends of the same specimens were subjected to compression tests. The data, recorded as load vs deflection, were converted into stress vs strain using the strength of materials formulae. The data obtained from the bending and the compression experiments were treated separately. The stiffness of the bones of the medicated groups were compared with those of the control groups. Our data indicated that the tamoxifen treated humera, femora and tibiae attained the largest bending stiffness in all cases investigated. However, this was not the case for compression. None of the drug administered groups attained the stiffness of the control group except for the case of tamoxifen treated femora which attained stiffness close to that of the controls. The results show that heparin altered the mechanical properties of bones indicating osteoporosis, tamoxifen was effective in reducing the effect of heparin while calcitonin yielded no conclusive result.

Animals↗
PubMed2002

Flexible docking of an acetoxyethoxymethyl derivative of thiosemicarbazone into three different species of dihydrofolate reductase.

Dihydrofolate reductases (DHFR) of human, Candida albicans and E coli were docked with their original ligands of X-ray crystal complex using QXP (Quick eXPlore), a docking program. Conditions to reproduce the crystal structures within the root mean square deviation (rmsd) of 2.00 A were established. Applying these conditions, binding modes and species-specificities of a novel antibacterial compound, N4-(2-acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone (AATSC), were studied. As the results, the docking program reproduced the crystal structures with average rmsd of six ligands as 0.91 A ranging from 0.49 to 1.45 A. The interactions including the numbers of hydrogen bonds and hydrophobic interactions were the same as the crystal structures and superposition of the crystal and docked structures almost coincided with each other. For AATSC, the results demonstrated that it could bind to either the substrate or coenzyme sites of DHFR in all three species with different degrees of affinity. It confirms the experimentally determined kinetic behavior of uncompetitive inhibition against either the inhibitor or the coenzyme. The docked AATSC overlapped well with the original ligands and major interactions were consistent with the ones in the crystal complexes. The information generated from this work should be useful for future development of antibacterial and antifungal agents.

Binding Sites↗
PubMed1999

Comparison of the flexible and standard laryngeal mask airways.

PURPOSE: To determine mucosal pressures, ease of insertion, mask position and oropharyngeal leak pressures for the flexible (FLMA) and standard laryngeal mask airway (LMA). METHODS: Forty anesthetized, paralysed adult patients were randomly allocated to receive either the FLMA or LMA. Microchip sensors were attached to the LMA or FLMA at identical locations corresponding to the base of tongue, hypopharynx, lateral pharynx, oropharynx, posterior pharynx and pyriform fossa. Mucosal pressure, oropharyngeal leak pressure (OLP) and mask position (assessed fibreoptically) were recorded during inflation of the cuff from 0-40 ml in 10 ml increments. RESULTS: Ease of insertion and mask position were similar between devices. Mean OLP was higher for the LMA (22 vs 19 cm H2O), but the maximum OLP was similar (25 vs 24 cm H2O). Mean mucosal pressures were generally low (< 12 cm H2O) for both devices, but were higher for the LMA in the lateral pharynx (4 vs 1 cm H2O) and oropharynx (13 vs 3 cm H2O) and higher in the posterior pharynx for the FLMA (4 vs 2 cm H2O). The OLP for both devices increased with increasing intracuff volume from 0-10 ml and 10-20 ml, and from 20-30 ml for the FLMA. CONCLUSIONS: We conclude that the LMA and FLMA perform similarly in terms of ease of insertion and mask position, but OLP and mucosal pressures are slightly higher for the LMA. Pharyngeal mucosal pressures for both devices are lower than those considered safe for the tracheal mucosa. The overall clinical performance between the two devices is similar.

Adolescent↗
PubMed2000

An application of generalizability theory to study a physical performance measure in Parkinson's disease.

Clinicians and researchers frequently quantify impairments and functional ability to monitor patient's symptoms and progress. For some patients, such as those with Parkinson's disease (PD), symptoms can fluctuate from day to day, making reliable measurement difficult. Multiple measures then may be required to obtain reliable data. Decisions must be made, balancing the optimum measurement schedule to obtain "good reliability" against burden to the patient. This investigation demonstrates the use of Generalizability Theory in determining the testing schedule when designing an experiment involving patients with known fluctuations of symptoms. In this investigation we use "Functional Axial Rotation" (FAR), a measure of spinal flexibility, to illustrate the use of Generalizability Theory for designing an experiment using participants who have PD. Measurements of FAR were taken on 13 participants, aged 60 or older, who were in early and mid-stages of PD. Three measurements were obtained on each of two consecutive days, and repeated on two consecutive days a week later, giving a total of 12 measures of FAR for each individual. Four sources of variation (subject, week, day and trial) were employed to estimate the reliability of FAR under several designs. Assuming different schedules of measures across weeks, days and trials, the estimated reliability of FAR for four measurements is in the range of 0.75 to 0.83, and for eight measurements in the range of 0.82 to 0.86. We discuss the use of this type of analysis in the determination of the optimum measurement design for experiments involving subjects with known fluctuations.

Analysis of Variance↗
PubMed2001

Myofascial flap without skin for intra-oral reconstruction. 2: Clinical studies.

BACKGROUND: Based on the results of our animal experiment, we evaluated the clinical usefulness of myofascial graft materials in the reconstruction of intra-oral soft-tissue defects. METHODS: An axial-pattern or random-pattern myofascial flap was grafted to reconstruct oral soft-tissue defects caused by tumor resection in ten patients. A pectoralis major myofascial flap was employed in four patients, and a platysma myofascial flap was employed in six patients. RESULTS: All flaps survived, and epithelialization progressed gradually from the surrounding incised mucosal margin. Cicatricial contracture of the wound seemed to be mild and the regenerated mucosa was more flexible than skin. Because the myofascial tissue had only raw surfaces, the handling of the flaps in the oral cavity was very flexible. Moreover, cosmetically unsatisfactory scar formation and dysfunction at the donor site were mild. CONCLUSION: We feel that the myofascial graft procedure is a very useful option for the reconstruction of intra-oral soft-tissue defects, and will soon become a common procedure. We refer to this procedure as the "biological-guided mucosa regeneration (BGMR)" technique.

Adult↗
PubMed2006

Protein flexibility: its role in structure and mechanism revealed by molecular simulations.

Computer simulations at the atomic level have arrived at a stage where they provide realistic modeling of flexibility in proteins (and the mobility of their associated solvent) that is important in understanding the nature of molecular motions. This can now be extended to the molecular and atomic motions that are associated with protein mechanisms. Moreover, the derived data agree reasonably accurately with experimental measurements of several kinetic and thermodynamic parameters. Fundamental insights emerge on the roles that this intrinsic flexibility plays in the thermodynamic characteristics of macromolecules in solution; these equip the investigator to probe the consequences of cognate interactions and ligand binding on entropy and enthalpy. Thus simulations can now provide a powerful tool for investigating protein mechanisms that complements the existing and the emerging experimental techniques.

Calmodulin↗
PubMed1999

Scaffolding proteins and their role in viral assembly.

Scaffolding proteins are proteins that are required to catalyse, regulate or modulate some step in the assembly of a macromolecular complex. They associate specifically with the nascent protein complex during assembly, but are subsequently removed, and are absent from the mature structure. Scaffolding proteins have been described primarily from viral systems, in particular from the double-stranded DNA bacteriophages, but most likely play a more general role in macromolecular assembly, a fundamental process in all biological systems. Scaffolding proteins may act in a specific fashion, by actively encouraging the formation of correct protein-protein interactions, or more generally by nucleating and promoting assembly. They may also work to ensure the fidelity of the assembly process by preventing the formation of improper interactions, in many ways similar to the role of molecular chaperones in protein folding. In viruses, scaffolding proteins are found both in the form of internal cores and external bracing, and may form elaborate and complex structures. This review will focus on the viral scaffolding proteins, for which an increasing amount of structural and functional information has recently become available.

Adenoviridae↗