Seminar by Hiroshi Imamura – University of Copenhagen

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Seminar by Hiroshi Imamura

Protein aggregation involved in evolution and biopharmaceutics

 

Hiroshi Imamura, Ritsumeikan University

 

    Anomalous physicochemical characters of proteins such as folding are given via molecular evolution. Tolerance to aggregation is also supposed to be special to naturally occurring proteins. To address this, we examined the artificially designed Cro protein that does not experience natural selection but folds into the structure of naturally occurring Cro protein. We found that only the artificial Cro aggregated [1]. We recently traced whale evolution by comparing the extant whale myoglobin with the ancestral whale myoglobins in terms of a self-interaction by a small angle X-ray scattering. The extant whale myoglobin avoids aggregation by modification of the self-interaction. This allows the extant whale to concentrate the oxygen supplier, myoglobin, in the muscle, which gives the deep-diving capacity.

    Increasing popularity of the therapeutic use of proteins, such as monoclonal antibody drugs, raises concerns about protein aggregation because aggregates are potentially immunogenic. The talk presents how the aggregates emerge and evolve. Static and dynamic light scattering indicated that the aggregates were fractal. The growth kinetics was well described by Smoluchowski aggregation equation that involves diffusion and collision with a certain probability given by an intermolecular interaction [2]. A fluorescence correlation spectroscopic analysis proved unfolding-bypassing aggregation was negligible in contrast to a well-appreciated mechanism in amyloid [3]. This model would be useful for improving the manufacturing process and predicting storage life of protein drugs.

 

[1] Imamura et al, Biochemistry 51, 3539, 2012.

[2] Imamura and Honda, J. Phys. Chem. B 120, 9581, 2016.

[3] Imamura et al, J. Phys. Chem. B 121, 8085, 2017.