Rational Design of Solution Additives for the Prevention of Protein Aggregation

Baynes, Brian M.; Trout, Bernhardt L.

doi:10.1529/biophysj.104.042473

Cited by 105 publications

(107 citation statements)

References 33 publications

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“…Related suggestions has previously been put forward [7,46]. The current results show that for BSA, the lyotropic properties of a solute (reflected in its position in the Hofmeister series [39]) are of minor importance both for the rate of the irreversible step and for the size and concentration of aggregate particles in heat-treated samples.…”

Section: Accepted Manuscriptsupporting

confidence: 71%

Solute effects on the irreversible aggregation of serum albumin

Bagger¹,

Ōgendal²,

Westh³

2007

Biophysical Chemistry

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 AbstractThermal stress on bovine serum albumin (BSA) promotes protein aggregation through the formation of intermolecular β-sheets. We have used light scattering and chromatography to study effects of (<1M) Na 2 SO 4 , NaSCN, sucrose, sorbitol and urea on the rate of the thermal aggregation. Both salts were strong inhibitors of BSA-aggregation and they reduced both the size and number (concentration) of aggregate particles compared to non-ionic solutes (or pure buffer). Hence, the salts appear to suppress both nucleation-and growth rate. The nonelectrolyte additives reduced the initial aggregation rate (compared to pure buffer), but did not significantly limit the extent of aggregation in samples quenched after 27 min. heat exposure

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Section: Accepted Manuscriptsupporting

confidence: 71%

Solute effects on the irreversible aggregation of serum albumin

Bagger¹,

Ōgendal²,

Westh³

2007

Biophysical Chemistry

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“…Arakawa and Tsumoto (2003) proposed that arginine suppresses protein aggregation during refolding. Arginine could also be preventing excessive nucleation by acting as a ''neutral crowder'' (Baynes and Trout 2004).…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of TM0549 and NE1324—two orthologs of E. coli AHAS isozyme III small regulatory subunit

et al. 2007

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Crystal structures of two orthologs of the regulatory subunit of acetohydroxyacid synthase III (AHAS, EC 2.2.1.6) from Thermotoga maritima (TM0549) and Nitrosomonas europea (NE1324) were determined by single-wavelength anomalous diffraction methods with the use of selenomethionine derivatives at 2.3 Å and 2.5 Å , respectively. TM0549 and NE1324 share the same fold, and in both proteins the polypeptide chain contains two separate domains of a similar size. Each protein contains a C-terminal domain with ferredoxin-type fold and an N-terminal ACT domain, of which the latter is characteristic for several proteins involved in amino acid metabolism. The ferredoxin domain is stabilized by a calcium ion in the crystal structure of NE1324 and by a Mg(H 2 O) 6 2+ ion in TM0549. Both TM0549 and NE1324 form dimeric assemblies in the crystal lattice.Keywords: acetohydroxyacid synthase; actolactate synthase; regulatory subunit; ACT domain; AHAS; protein refolding Acetohydroxyacid synthase (AHAS, EC 2.2.1.6) catalyzes two physiologically significant reactions in the synthesis of isoleucine, valine, and leucine. In the first reaction, which is an initial step in the synthesis of isoleucine, 2-aceto-2-hydroxy butyrate is produced by condensation of 2-ketobutyrate with pyruvate. In the second reaction, 2-acetolactate is synthesized from two pyruvate molecules, and this provides substrates for synthesis of valine and leucine (Umbarger 1978(Umbarger , 1987Chipman et al. 1998). This pathway of branched-chain amino acid biosynthesis is characteristic for bacteria, fungi, algae, and higher plants, but not for animals. Accordingly, AHAS inhibitors have been developed as herbicides which have found broad application (Short and Colborn 1999). The inhibitors of branched-chain amino acids synthesis are also being tested as potential antituberculosis agents (Grandoni et al. 1998;Zohar et al. 2003;Choi et al. 2005).Three different FAD-dependent AHAS isozymes (I, II, and III) are found in enterobacteria (e.g., Escherichia ), but most other organisms from the bacteria encode only a single AHAS enzyme, similar to isozyme III from E. coli. The acetohydroxyacid synthases are multimeric proteins, and most frequently their biological unit is composed of two catalytic subunits (CSU) and two small regulatory subunits (SSU). In the absence of the SSU subunit, the CSU dimer is unstable (Vyazmensky et al. 1996), suggesting that in the holoenzyme the AHAS dimer is stabilized by a SSU dimer. The large catalytic subunits also show very weak activity without their associated regulatory subunits (Weinstock et al. 1992;Pang and Duggleby 1999). The E. coli AHAS enzyme can be reconstituted with SSU subunits from other organisms (Porat et al. 2004), and the reconstituted enzymes form stable heterotetramers. The properly associated holoenzymes show full catalytic activity, and are also susceptible to valine inhibition.Previous mutagenesis studies (Mendel et al. 2001;Kaplun et al. 2006) revealed that the valine binding sites are located at the dimerizatio...

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“…For aggregation in the presence of kosmotropes, we hypothesize that depletion interactions accelerate aggregation (58,59). Depletion interaction arises when a solute molecule (a hydrated , and sulfate (E).…”

Section: Discussionmentioning

confidence: 99%

Ion-specific Effects on Prion Nucleation and Strain Formation

Rubin

Khosravi

Bruce

et al. 2013

Journal of Biological Chemistry

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Background: Prion proteins may adopt multiple aggregate conformations, known as strains. Results: Kosmotropic and chaotropic anions exhibit opposite effects on aggregation kinetics and favor different strains. Conclusion: Both prion nucleation kinetics and prevailing strain patterns strongly depend on ionic composition of the aggregation mixture. Significance: Ionic composition is shown to be a critical determinant in the generation of prion strains.

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Rational Design of Solution Additives for the Prevention of Protein Aggregation

Cited by 105 publications

References 33 publications

Solute effects on the irreversible aggregation of serum albumin

Solute effects on the irreversible aggregation of serum albumin

Crystal structures of TM0549 and NE1324—two orthologs of E. coli AHAS isozyme III small regulatory subunit

Ion-specific Effects on Prion Nucleation and Strain Formation

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