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PubMed1992

Stabilization of acetylcholine receptors at the neuromuscular synapse: the role of the nerve.

The majority of acetylcholine receptors (AChRs) at innervated neuromuscular junctions (NMJs) are stable, with half-lives averaging about 11 days in rodent muscles. In addition to the stable AChRs, approximately 18% of AChRs at these innervated junctions are rapidly turned over (RTOs), with half lives of less than 24 h. We have postulated that RTOs may be precursors of stable AChRs, and that the motor nerve may influence their stabilization. This hypothesis was tested by: (i) labeling AChRs in mouse sternomastoid (SM) muscles with 125I-alpha-BuTx; (ii) denervating one SM muscle in each mouse, and (iii) following the fate of the labeled AChRs through a 5-day period when RTOs were either stabilized or degraded. The hypothesis predicts that denervation should preclude stabilization of RTOs, resulting in a deficit of stable AChRs in denervated muscles. The results showed a highly significant (P less than 0.002) deficit of stable AChRs in denervated as compared with innervated muscles. Control experiments excluded the possibility that this deficit could be attributed to independent accelerated degradation of either RTOs or pre-existing stable AChRs. The observed deficit was quantitatively consistent with the deficit predicted by a mathematical model based on interruption of stabilization following denervation. We conclude that: (i) the observed deficit after denervation of NMJs is due to failure of stabilization of pre-existing RTOs; (ii) RTOs at normally innervated NMJs are precursors of stable AChRs; (iii) stabilization occurs after the insertion of AChRs at NMJs, and (iv) motor nerves play a key role in stabilization of RTOs. The concept of receptor stabilization has important implications for understanding the biology of the neuromuscular junction and post-synaptic plasticity.

Animals↗

PubMed1980

Effects of fracture stabilization by internal fixation. I. A haemodynamic and blood gas evaluation of the systemic and regional changes.

The effect of internal stabilization of a fracture of the femur on arterial blood oxygen levels, limb flow and oxygen consumption was measured in 24 dogs. Those with stabilized fractures bore weight on their limbs and were much more active. Without fracture stabilization the arterial oxygen tension fell by 10 per cent. With internal fixation this hypoxia did not develop. In fact, there was a 10 per cent increase beginning in the third week. Stabilization of the fracture gave a persistent increase in limb blood flow, but without stabilization this increase was transient and followed by a significant decrease. Over the 7-week observation period, the total oxygen consumption of the uninjured limbs in the stabilized group was twice that in the unstabilized group, an indication of their functional activity. Also with stabilization, the oxygen consumption of the uninjured limb was not significantly different from the opposite limb, whereas without stabilization the consumption was 32 per cent greater, an indication of the energy cost of countering instability.

Animals↗

PubMed1992

Effect of active site residues in barnase on activity and stability.

We have mutated residues in the active site of the ribonuclease, barnase, in order to determine their effects on both enzyme activity and protein stability. Mutation of several of the positively charged residues that interact with the negatively charged RNA substrate (Lys27----Ala, Arg59----Ala and His102----Ala) causes large decreases in activity. This is accompanied, however, by an increase in stability. There is presumably electrostatic strain in the active site where positively charged side-chains are clustered. Mutation of several residues that make hydrogen bonds (Ser57----Ala, Asn58----Asp and Tyr103----Phe) causes smaller decreases in activity, but increases or has no effect on stability. Deletion of hydrogen bonding groups elsewhere in proteins has been found previously to decrease stability by 0.5 to 1.5 kcal mol-1. Conversely, we find that two mutations (Asp54----Asn and Gln104----Ala) decrease stability and increase activity. Another mutation (Glu73----Ala) decreases both activity and stability. It is clear that many residues in the active site do not contribute to stability and that for some, but not all, of the residues there is a compromise between activity and stability. This suggests that certain types of local instability may be necessary for substrate binding and catalysis by barnase. This has implications for the understanding of enzyme activity and the design of enzymes.

Bacillus↗

PubMed1990

Effect of L-carnitine and acetyl-L-carnitine on the human erythrocyte membrane stability and deformability.

In this study we examined the effect of carnitine and acetylcarnitine on the human erythrocyte membrane stability and membrane deformability. Since erythrocyte membranes are impermeable to these compounds, we resealed erythrocyte ghosts in the presence of different concentrations of carnitine or acetylcarnitine. Resealed ghosts can be adequately studied in their cellular deformability and membrane stability properties by means of ektacytometry. Both carnitine and acetylcarnitine alter the membrane stability but not membrane deformability of the red cell membrane. Resealed ghosts containing 20, 50, 150, and 300 microM carnitine had 1.1, 1.6, 0.9, and 0.7 times the normal stability. While resealed ghosts containing 20, 50, 150, and 300 microM acetylcarnitine had 1.1, 1.5, 1.3, and 1.2 times the normal stability. Such changes were found to be reversible. We also conducted SDS PAGE of cytoskeletal membrane proteins from membrane fragments and residual membranes produced during membrane stability analysis, and unsheared resealed membranes in those samples where we observed an increase or a decrease of membrane stability. No changes in the cytoskeletal membrane proteins were noticed, even when the samples, prior SDS PAGE analysis, were treated with or without dithiothreitol. In addition, fluorescence steady state anisotropy of DPH in the erythrocyte membrane treated with carnitine or acetylcarnitine shows no modification of the lipid order parameter. Our results would suggest that both carnitine and its acetyl-ester, at physiological concentrations, may increase membrane stability in mature erythrocytes, most likely via a specific interaction with one or more cytoskeletal proteins, and that this effect would manifest when the erythrocytes are subjected to high shear stress.

Acetylcarnitine↗

PubMed1991

Sequence specific thermal stability of the collagen triple helix.

Theoretical calculations of the thermal stability of collagen triple helices using empirical values for the contribution of individual tripeptide units are presented and compared with direct measurements of the thermal stability of various types of collagens. Relative stabilities are assigned to the positions of the tripeptide units in the amino acid sequence along the length of the collagen molecule. The sequence specific relative stabilities of type I and type XI collagens are compared. These offer insight into the reasons for the existence of unfolding intermediates in type XI collagen that are absent in type I collagen. The pattern of relative stabilities calculated for mouse type IV collagen is consistent with experimental results which indicate that the amino terminal region is very stable and that the interruptions cause increased flexibility and independently unfolding domains. Mutations in the triple helical domain of human type I procollagen occurring in brittle bone disease (osteogenesis imperfecta) show varying effects on the thermal stability of the molecule. The sequence specific thermal stability calculations shed some light on why some mutations of cysteine for glycine have greater effects on the thermal stability than others.

Amino Acid Sequence↗

PubMed1995

Fracture line stability as a function of the internal fixation system: an in vitro comparison using a mandibular angle fracture model.

PURPOSE: This study was conducted to determine and compare the initial mechanical stability and functional capability of six contemporary internal fixation systems used to fix mandibular angle fractures. MATERIALS AND METHODS: An iterative analog of a mandibular angle fracture was developed to ensure replicability of material properties and fracture configuration across the test constructs. Each of six sets of mandible analog (1 set = 3 mandibles) was reduced according to prescribed technique by a variety of compressive and adaptive fixation systems. The compressive systems included the 1) eccentric dynamic compression plate, 2) Würzburg plate, 3) Luhr plate, and 4) solitary lag screw technique. The Champy miniplate and the Mennen clamp plate represented the adaptive fixation systems. The reduced analogs were placed in a straining frame, and simulated masticatory loads were applied to predetermined occlusal sites. Fracture line displacements were acquired and registered by displacement transducers attached to a computer-based data acquisition program. A coordinate transformation procedure was used to convert the generalized displacements at the fracture line into the individual rotations of the segments. An "instability factor" computed from the force-displacement data recorded at various loading conditions for each test construct was used to characterize a particular system's ability to restrain relative motion at the fracture surfaces. RESULTS: There were minimal variations in the stability profiles of the individual compressive fixation systems. However, the fixation stability provided by the compressive and adaptive systems differed significantly (P < or = .0001). A large initial setting and a susceptibility to variations in loading patterns characterized the functional stability provided by the adaptive systems. Even at low masticatory loads (2 DaN), the adaptive systems had an instability that was two to three times as much as that of the compressive systems. Post-hoc comparisons between pairs of devices showed that angle fractures fixed by compressive systems provided significantly greater stability (P < or = .05) than those fixed by the Champy and Mennen systems. Between the adaptive systems tested, fracture fixation with Mennen plates was more stable than reduction by Champy miniplates (P < or = .05) when averaged over loads. CONCLUSIONS: Compressive fixation systems are biomechanically superior to adaptive systems and provide good immediate functional stability to reduced mandibular angle fractures. The Champy and Mennen systems permit significantly higher motion at the fracture site, even at the attenuated masticatory forces encountered in the early postoperative period. Because the functional stability afforded by these adaptive systems is influenced by variations in the biting patterns, the risk of infection and complicated healing is correspondingly increased. Also, the low displacement resistance of the adaptive systems may not protect the alignment of the mandibular segments through the healing period and may manifest as occlusal discrepancies in the dentate patient. The biomechanical test system developed for this study allows an equitable comparison of fixation stability and appears to be a promising tool for investigating a variety of fixation systems and optimizing device design on a rational basis.

Analysis of Variance↗

PubMed2004

Stabilization of tumor necrosis factor-alpha mRNA in macrophages in response to chronic ethanol exposure.

Tumor necrosis factor-alpha (TNF-alpha) is one of a number of cytokines implicated in the progression of alcohol-induced liver disease. Activation of hepatic macrophages by lipopolysaccharide (LPS) during exposure to ethanol is thought to be an important mechanism for stimulation of TNF-alpha expression. Chronic exposure of macrophages to ethanol, both in vivo after ad libitum feeding of ethanol for 4 weeks and in culture for 48 h, has an impact on specific elements within the LPS-stimulated signaling cascade, disrupting both transcriptional and posttranscriptional regulation of TNF-alpha biosynthesis. Stabilization of TNF-alpha mRNA after chronic exposure to ethanol is one important mechanism for increased TNF-alpha production by hepatic macrophages. Increased LPS stimulation of p38 mitogen-activated protein kinase contributes to this stabilization of TNF-alpha mRNA in macrophages. Stabilization of TNF-alpha mRNA after chronic exposure to ethanol requires both cis-acting elements in the TNF-alpha mRNA and trans-acting mRNA-binding proteins. The adenosine plus uridine-rich element in the 3' untranslated region of the TNF-alpha mRNA is an important regulator of TNF-alpha mRNA stability. Its activity is required for stabilization of TNF-alpha mRNA induced by chronic exposure to ethanol. Moreover, results from studies have demonstrated that at least one mRNA-binding protein, HuR, is also involved in stabilization of TNF-alpha mRNA stability after chronic exposure to ethanol. Taken together, the results from these studies identify the regulation of TNF-alpha mRNA stability as a novel mechanism by which chronic exposure to ethanol increases the expression of TNF-alpha.

Animals↗

PubMed2006

Increased SOCS6 stability with PMA requires its N-terminal region and the Erk pathway via Pkcdelta activation.

We investigated stability of the ectopically expressed the SOCS6 protein in HEK293T cells with PMA, which activates protein kinase C (PKC). The treatment of PMA could largely increase SOCS6 stability in HEK293T cells. But, we did not observe increased protein levels of SOCS3 or Erk1 with PMA. This result suggests that the increased stability of SOCS6 with PMA did not generally occur in other proteins. The stability of SOCS6 depended on the N-terminal region containing an unidentified domain. We then studied the role of signal pathways in SOCS6 stability with PMA. We found that both Erk and Pkcdelta activation were required for the increased SOCS6 stability by PMA. The Erk activation by PMA appeared to be downstream from the Pkcdelta activation. The increased SOCS6 stability and Erk activation by PMA were both conserved in another cell line, MCF7. In addition, we demonstrated that PMA, insulin, and PDGF increased both the stability of endogenous-expressed SOCS6 and Erk activation in MDA-MB231 cells. These observations suggest that Erk activation may be correlated in the cells with high expression of SOCS6.

Cell Line↗

PubMed2005

Relative importance of secondary structure and solvent accessibility to the stability of protein mutants. A case study with amino acid properties and energetics on T4 and human lysozymes.

Understanding the factors influencing the stability of protein mutants is an important task in molecular and computational biology. In this work, we have approached this problem by examining the relative importance of secondary structure and solvent accessibility of the mutant residue for understanding/predicting the stability of protein mutants. We have used hydrophobic, electrostatic and hydrogen bond free energy terms and nine unique physicochemical, energetic and conformational properties of amino acids in the present study and these parameters have been related with changes in thermal stability (DeltaTm) of all the single mutants of lysozymes based on single and multiple correlation coefficients. As expected the properties reflecting hydrophobicity and hydrophobic free energy play a major role to distinguish stabilizing and destabilizing mutants. The hydrophobic free energy due to carbon and nitrogen atoms distinguish the stability of coil and strand mutations to the accuracy of 100 and 90%, respectively. In agreement with previous results, the subgroup classification based on secondary structure and the information about its location in the structure yielded good relationship with the experimental DeltaTm. We revealed that the secondary structure information is equally or more important than solvent accessibility for understanding the stability of protein mutants. The comparison of amino acid properties with free-energy terms indicate that the energetic contribution explains the mutant stability better in coil region whereas the amino acid properties do better in strand region. Further, the combination of free energies with amino acid properties increased the correlation significantly. The present study demonstrates the importance of classifying the mutants based on secondary structure to the stability of proteins upon mutations.

Amino Acids↗

PubMed2005

Stability and variability may respond differently to changes in walking speed.

In gait research it has often been assumed that variability and stability are negatively correlated, where increases in variability are assumed to equate with increases in instability. The purpose of this paper is to illustrate that variability does not always equate with stability. To proof this point, a method was developed to directly assess stability and variability during the application of a visual perturbation at different walking speeds. Walking variability was measured by using the average standard deviation of the knee joint angle across the gait cycle. Walking stability was measured by the recovery time of the knee joint angle trajectory from the distortion induced by a visual perturbation that was delivered at the beginning of the stance phase. Five participants were required to walk at six different velocities on a treadmill (0.67, 0.80, 0.94, 1.07, 1.21, and 1.34 m/s). The coefficients of intraclass correlations for the experiment were 83% and 80% for the calculated stability and variability, respectively. The calculated stabilities were not sensitive to changes in walking speed (p>0.98). The calculated variability however decreased with increases in walking speed (p=0.004). No significant correlation between variability and stability was observed (r=-0.002). We suggest that gait stability is independent of variability during locomotion and should thus be measured independently.

Acceleration↗

PubMed2004

Soft-tissue stabilizers of the distal radioulnar joint: an in vitro kinematic study.

PURPOSE: Distal radioulnar joint (DRUJ) stability is dependent on osseous anatomy, soft-tissue stabilizers, and muscle activity. The relative importance of DRUJ soft-tissue stabilizers remains controversial and has not been examined in the more physiologic setting of simulated muscle loading in the intact specimen. The purpose of this study was to examine the role of static stabilizers on the kinematics of the DRUJ during active simulated motion. METHODS: Twelve cadaveric upper extremities underwent computer-controlled, simulated, active forearm rotation. Joint kinematics were measured in the intact specimen and after sequential sectioning of soft-tissue stabilizers including the dorsal and palmar radioulnar ligaments (RULs) and the triangular fibrocartilage (TFC), dorsal and palmar capsule, ulnocarpal ligaments (UCL), extensor carpi ulnaris (ECU) subsheath, pronator quadratus (PQ), and the interosseous membrane (IOM). RESULTS: After sectioning of soft tissues significant changes in the DRUJ kinematics were observed. With a distal to proximal sectioning sequence significant alterations in kinematics were not identified until sectioning of the IOM; with a proximal to distal sectioning sequence intact DRUJ kinematics were maintained until the final soft-tissue (RULs and TFC) sectioning. CONCLUSIONS: Sectioning of all soft-tissue stabilizers produced significant DRUJ instability and abnormal joint kinematics. The RULs and TFC play a key role in DRUJ kinematics because they can help to maintain normal joint rotation in the absence of all other soft-tissue stabilizers. With the preservation of other soft-tissue stabilizers, however, the RULs and TFC are not essential for the maintenance of normal kinematics of the DRUJ.

Adult↗

PubMed2006

Role of the charge-charge interactions in defining stability and halophilicity of the CspB proteins.

Charge-charge interactions on the surface of native proteins are important for protein stability and can be computationally redesigned in a rational way to modulate protein stability. Such computational effort led to an engineered protein, CspB-TB that has the same core as the mesophilic cold shock protein CspB-Bs from Bacillus subtilis, but optimized distribution of charge-charge interactions on the surface. The CspB-TB protein shows an increase in the transition temperature by 20 degrees C relative to the unfolding temperature of CspB-Bs. The CspB-TB and CspB-Bs protein pair offers a unique opportunity to further explore the energetics of charge-charge interactions as the substitutions at the same sequence positions are done in largely similar structural but different electrostatic environments. In particular we addressed two questions. What is the contribution of charge-charge interactions in the unfolded state to the protein stability and how amino acid substitutions modulate the effect of increase in ionic strength on protein stability (i.e. protein halophilicity). To this end, we experimentally measured the stabilities of over 100 variants of CspB-TB and CspB-Bs proteins with substitutions at charged residues. We also performed computational modeling of these protein variants. Analysis of the experimental and computational data allowed us to conclude that the charge-charge interactions in the unfolded state of two model proteins CspB-Bs and CspB-TB are not very significant and computational models that are based only on the native state structure can adequately, i.e. qualitatively (stabilizing versus destabilizing) and semi-quantitatively (relative rank order), predict the effects of surface charge neutralization or reversal on protein stability. We also show that the effect of ionic strength on protein stability (protein halophilicity) appears to be mainly due to the screening of the long-range charge-charge interactions.

Amino Acid Sequence↗

PubMed2004

Complexity and demographic stability in population models.

This article is concerned with relating the stability of a population, as defined by the rate of decay of fluctuations induced by demographic stochasticity, with its heterogeneity in age-specific birth and death rates. We invoke the theory of large deviations to establish a fluctuation theorem: The demographic stability of a population is positively correlated with evolutionary entropy, a measure of the variability in the age of reproducing individuals in the population. This theorem is exploited to predict certain correlations between ecological constraints and evolutionary trends in demographic stability, namely, (i) bounded growth constraints--a uni-directional increase in stability, (ii) unbounded growth constraints (large population size)--a uni-directional decrease in stability, (iii) unbounded growth constraints (small population size)--random, non-directional change in stability. These principles relating ecological constraints with trends in demographic stability are shown to be far reaching generalizations of the tenets derived from classical studies of stability in an evolutionary context. These results thus provide a new conceptual framework for explaining patterns of variation in population numbers observed in natural populations.

Age Factors↗

PubMed1997

Safe and effective method of stabilization for coronary artery bypass grafting on the beating heart.

BACKGROUND: There is an emerging interest in performing coronary artery bypass grafting on the beating heart. This study examines the efficacy and safety of two types of coronary artery stabilizers developed to perform coronary artery bypass grafting on the beating heart. METHODS: Four dogs underwent left internal mammary artery to left anterior descending artery anastomosis using a retractor-fixed stabilizer. Measurements of hemodynamic indices and range of motion of the targeted arteriotomy were done before and after application of the stabilizers. Patency of the anastomosis was evaluated by angiography. To clinically validate the safety of this stabilizer, we collected data on 150 patients from centers that had access to the retractor-fixed stabilizer. RESULTS: All animals survived the procedure with no ischemic changes or hemodynamic alterations. A significant reduction in range of motion (mm) of the left anterior descending coronary artery was achieved after application of the stabilizers. Angiographic studies showed good anastomotic patency. Histologic examination showed no myocardial injury. Patient data revealed successful completion of the anastomosis, with conversion to sternotomy or cardiopulmonary bypass in 1 patient each. Intraoperative and postoperative myocardial infarctions occurred in 1 patient each, with one in-hospital death. CONCLUSIONS: Significant stabilization of targeted coronary arteries allowing the performance of safe and reliable anastomosis on a beating heart can be achieved using the stabilizer.

Adult↗

PubMed1996

Exercise effect on dynamic stability in older women: a randomized controlled trial.

OBJECTIVE: To determine whether a 12-month program of regular exercise can improve dynamic postural stability in older women. DESIGN: Randomized controlled trial of 12 months' duration. SETTING: Conducted as part of the Randwick Falls and Fractures Study, in Sydney, Australia. PARTICIPANTS: One hundred and twelve community-dwelling women aged 60 to 85 years (mean age 71.2, SD = 5.4). OUTCOME MEASURES: Quantitative measures of dynamic postural stability: maximal balance range and coordinated stability. MAIN RESULTS: Exercise and control subjects were tested before, midway through, and at the end of the trial. The stability measures had good test-retest reliability, and test performances were significantly associated with measures of lower limb muscle strength, reaction time, neuromuscular control, and body sway. At initial testing, exercisers and controls performed similarly in the two stability measures. The mean number of classes attended for the 48 exercise subjects who completed the program was 58.4 (range 26-77). At the end of the trial, the exercise subjects showed significantly improved performance in both the maximal balance range and coordinated stability tests, with no improvement evident in the controls. Improvements in coordinated stability were associated with corresponding improvements in ankle dorsiflexion, hip extension, and hip flexion strength. CONCLUSION: These findings show that exercise can significantly improve dynamic postural stability in older persons and elucidate some possible mechanisms by which such improvements may be mediated.

Accidental Falls↗

PubMed2002

Increasing protein stability by polar surface residues: domain-wide consequences of interactions within a loop.

We have examined the influence of surface hydrogen bonds on the stability of proteins by studying the effects of mutations of human immunoglobulin light chain variable domain (V(L)). In addition to the variants Y27dD, N28F, and T94H of protein kappa IV Len that were previously described, we characterized mutants M4L, L27cN, L27cQ, and K39T, double mutant M4L/Y27dD, and triple mutant M4L/Y27dD/T94H. The triple mutant had an enhanced thermodynamic stability of 4.2 kcal/mol. We determined the structure of the triple mutant by x-ray diffraction and correlated the changes in stability due to the mutations with changes in the three-dimensional structure. Y27dD mutant had increased stability of Len by 2.7 kcal/mol, a large value for a single mutation. Asp27d present in CDR1 formed hydrogen bonds with the side-chain and main-chain atoms within the loop. In the case of the K39T mutant, which reduces stability by 2 kcal/mol, Lys39 in addition to forming a hydrogen bond with a carbonyl oxygen of a neighboring loop may also favorably influence the surface electrostatics of the molecule. We showed that hydrogen bonds between residues in surface loops can add to the overall stability of the V(L) domains. The contribution to stability is further increased if the surface residue makes more than one hydrogen bond or if it forms a hydrogen bond between neighboring turns or loops separated from each other in the amino acid sequence. Based on our experiments we suggest that stabilization of proteins might be systematically accomplished by introducing additional hydrogen bonds on the surface. These substitutions are more straightforward to predict than core-packing interactions and can be selected to avoid affecting the protein's function.

Amino Acid Sequence↗

PubMed1998

Use of clomiphene citrate in the treatment of men with high sperm chromatin stability.

OBJECTIVE: To determine whether improvements of the seminal vesicle function after a 5-day course with clomiphene citrate (CC) may reduce the prevalence of men with high sperm chromatin stability under conditions of sodium dodecyl sulfate (SDS)-ethylenediaminetetraacetic acid (EDTA). DESIGN: A prospective study. SETTING: Andrology laboratory at the Instituto de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Lima, Peru. PATIENT(S): Forty-one male partners of infertile couples attending the andrology laboratory. INTERVENTION(S): Clomiphene citrate was administered orally twice a day. Men were treated with CC at 100 mg daily for 5 days. Blood and semen samples were collected before treatment and 24 hours after the last administration. MAIN OUTCOME MEASURE(S): Serum testosterone, seminal fructose, sperm motility, sperm chromatin stability after SDS and EDTA, and prevalence of high sperm chromatin stability. RESULT(S): The percentage of stable sperm after SDS-EDTA correlated inversely with the basal corrected concentration of seminal fructose (-1.77 +/- 0.89, beta +/- SE). High sperm chromatin stability was observed in 53.8% of the study population and in 66.7% of patients with hypofunction of the seminal vesicles. In those men whose seminal vesicle function improved after treatment with CC, the prevalence of high sperm chromatin stability was reduced from 67% to 25% (chi2 = 5.34). Logistic regression analysis showed that the higher the basal corrected seminal fructose levels and the higher the basal serum testosterone levels, the lower the probability of nonresponse of the sperm chromatin stability to treatment with CC (0.54 +/- 0.15, odds ratio +/- SE for corrected fructose; and 0.50 +/- 0.15, odds ratio +/- SE for serum testosterone). CONCLUSION(S): Hypofunction of the seminal vesicles was associated with high sperm chromatin stability, and this high sperm chromatin stability under SDS-EDTA conditions may be reduced by treatment with CC.

Adolescent↗

PubMed2002

Quantifying beta-sheet stability by phage display.

The small immunoglobulin G (IgG)-binding protein GB1 is a favored model system for the study of individual residue contributions to the stability of beta-sheets. Nevertheless, only a few of the many possible combinations of mutations have been characterized, leaving many questions unanswered. In order to allow the simultaneous evaluation of libraries of mutants, we have adapted a phage-display method, called shotgun scanning. This method combines a binding (i.e. stability) selection with high-throughput sequence analysis. Relative folding free energies determined from GB1-phage sequence data agree well with published GB1 thermal stability studies, validating the use of phage display to conduct quantitative stability studies on GB1, and further suggesting that this method is generally applicable to mutational analysis of protein stability. Examination of residue pairing in our large collection of GB1 mutants indicates that specific side-chain-side-chain interactions are much less important to beta-sheet stability than individual residue contributions. The discrepancy between this observation and published studies can be traced to anomalous stability of the alanine-substituted GB1 variants typically used as reference states in double mutant-cycle analyses. Finally, the combination of large library sizes and a quantitative stability selection should allow phage-based "computation" to be applied to protein design problems.

Bacteriophages↗