Structural hot spots for the solubility of globular proteins

Nature Communications
Ashok GanesanJoost Schymkowitz

Abstract

Natural selection shapes protein solubility to physiological requirements and recombinant applications that require higher protein concentrations are often problematic. This raises the question whether the solubility of natural protein sequences can be improved. We here show an anti-correlation between the number of aggregation prone regions (APRs) in a protein sequence and its solubility, suggesting that mutational suppression of APRs provides a simple strategy to increase protein solubility. We show that mutations at specific positions within a protein structure can act as APR suppressors without affecting protein stability. These hot spots for protein solubility are both structure and sequence dependent but can be computationally predicted. We demonstrate this by reducing the aggregation of human α-galactosidase and protective antigen of Bacillus anthracis through mutation. Our results indicate that many proteins possess hot spots allowing to adapt protein solubility independently of structure and function.

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Citations

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Methods Mentioned

BETA
protein folding
size exclusion chromatography
dynamic light scattering
infrared spectroscopy
electrophoresis
circular dichroism
light scattering
ELISA
PCR
FCS

Software Mentioned

TANGO
studio
Micro
COOT
GenScript
Wyatt Dynamics
Quantity One
FoldX
Gal
Eurogentec

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