Thermal aggregation of α-chymotrypsin: Role of hydrophobic and electrostatic interactions

Rezaei‐Ghaleh, Nasrollah; Ramshini, Hossein; Ebrahim‐Habibi, Azadeh; Moosavi-Movahedi, Ali Akbar; Nemat‐Gorgani, Mohsen

doi:10.1016/j.bpc.2007.10.001

Cited by 39 publications

(43 citation statements)

References 56 publications

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“…Such a lag time has been observed in the aggregation of many proteins, including acidic fi broblast growth factor (aFGF) at pH 7.4, 76 recombinant human interleukin -1 receptor antagonist (rhIL -1ra ) at pH 6.5, 77 α -chymotrypsin (CT) under thermal stress, 78 apomyoglobin in aqueous urea solutions, 79 and fi refl y luciferase at pH 7.5. 80 The lag phase can take as long as several days depending on the solution conditions, such as aggregation of α -synuclein at 1 mg/mL.…”

Section: Aggregation Nucleationmentioning

confidence: 99%

“…182 This effect of aggregation inhibition by chaperone proteins has been shown to act through the binding of the protein to denatured monomers or short oligomers upon heating, forming relatively small and highly soluble complexes, 214 or specifi cally through hydrophobic interactions. 78,213 Another commonly examined chaperone protein is the family of crystallins. α -Crystallin was shown to inhibit thermal (65 ° C) aggregation of CT in a concentration -dependent manner.…”

Section: Amphoteric Polymers/proteinsmentioning

confidence: 99%

“…α -Crystallin was shown to inhibit thermal (65 ° C) aggregation of CT in a concentration -dependent manner. 78 It was also shown to signifi cantly inhibit aggregation of purifi ed β H -crystallin and precipitation of purifi ed β L -and γ -crystallin at pH 7.0 at 37 ° C. 218 Similar chaperone activity was also reported for α -B -crystallin, which can inhibit the aggregation of amyloid fi bril forming protein α -synucleinA53T. 32 Protein aggregation can be inhibited by rationally designed peptides.…”

Section: Amphoteric Polymers/proteinsmentioning

confidence: 99%

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External Factors Affecting Protein Aggregation

Wang

Speaker

2010

Aggregation of Therapeutic Proteins

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The behavior of biotherapeutic proteins is signifi cantly different from small molecule drugs both in liquid and solid states, especially in terms of physical stability. One such property is the high tendency of protein molecules to aggregate under a variety of conditions. The aggregation tendency is arguably the most common and troubling manifestation of protein instability during the development of protein biotherapeutics. 1 Protein aggregates usually exhibit either reduced or, in many cases, no biological activity. 2 -5 A clear correlation was established between loss of recombinant factor VIII (rFVIII ) and its degree of aggregation as shown in Fig. 4.1 . 6 To achieve effective prevention or inhibition of protein aggregation, it is of paramount importance to understand all the possible factors that affect or control the protein aggregation process.Many factors have been identifi ed and reported in the literature affecting the process and rate of protein aggregation. These factors can be roughly divided into two major categories: internal (protein structure related) and external (protein environment related). Chapter 3 in this book has focused extensively on factors that belong to the fi rst category. This chapter focuses on the external factors that affect the process and rate of protein aggregation. To facilitate discussion, these external factors are further divided into the following sections: (1) temperature; (2) solution conditions and composition (pH, buffer type and concentration, ionic strength, excipients and level, protein concentration, metal ions, denaturing and reducing agents, impurities, organic solvents, containers/closures, sources of proteins, sample treatment, and analytical methodologies); (3) processing steps (fermentation/expression,

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Section: Aggregation Nucleationmentioning

confidence: 99%

Section: Amphoteric Polymers/proteinsmentioning

confidence: 99%

Section: Amphoteric Polymers/proteinsmentioning

confidence: 99%

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External Factors Affecting Protein Aggregation

Wang

Speaker

2010

Aggregation of Therapeutic Proteins

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“…The opposite effects of kosmotropic and chaotropic anions, and the beneficial effect of chaperone-like compounds such as alpha-crystallin (which binds to hydrophobic patches of the unfolded enzyme molecules) have been observed [109]. Existence of patches of positive charges was suggested to be of importance in this process, since chemical modification of lysine residues was shown to reverse lack of protein aggregation observed at acidic pH [109].…”

Section: Chaperone-like Substancesmentioning

confidence: 99%

Protein-Protein interactions leading to aggregation: Perspectives on mechanism, significance and control

Ebrahim‐Habibi

Morshedi

Rezaei‐Ghaleh

et al. 2010

JICS

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Protein aggregates, whether amorphous or structured (amyloid), have attracted much attention in recent years and despite extensive efforts, the mechanism of their formation is poorly understood. While "natural" aggregation (polymerization) of monomers could improve the biological function of some proteins, it is usually the darker side of this phenomenon which is discussed in many studies: deleterious aggregation that could lead to loss of biological activity under in vitro conditions or cause misfolding diseases. In this review, protein aggregation has been overviewed, starting from some general concepts involved in its formation, followed by mentioning studies aimed at elucidation of its kinetics and mechanism, or characterization of intermediates that would be aggregation-prone, and finally, reporting some of the studies related to the design of methods that would control the process. Similarly, amyloid aggregates have been defined, and current methods used in their characterization have been briefly described, with an emphasis on in silico studies. Finally, identification and design of such molecules which may be effective in control of this process is discussed.

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“…The hydrophobic interaction has long been considered the primary stabilizing force present in the folded protein [22][23][24][25], but not in the unfolded protein; it undoubtedly accounts for the heat capacity change on folding, and its favorable contribution to the free-energy change may be estimated from the accessible surface area buried in the folded state. Hydrophobicity 2 also plays a major role in self-association of protein molecules.…”

Section: Hydrophobic Effectmentioning

confidence: 99%