ArticleScientific reports2015
Rational stabilization of complex proteins: a divide and combine approach.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Calculation of Protein Folding Thermodynamics Using Molecular Dynamics Simulations.Journal of chemical information and modeling · 2023Article
- Protein Stability: Enhancement and Measurement.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Protposer: The web server that readily proposes protein stabilizing mutations with high PPV.Computational and structural biotechnology journal · 2022Article
- The Stability Landscape of de novo TIM Barrels Explored by a Modular Design Approach.Journal of molecular biology · 2021Article
- Unravelling the Complex Denaturant and Thermal-Induced Unfolding Equilibria of Human Phenylalanine Hydroxylase.International journal of molecular sciences · 2021Article
- Interactions and cooperativity between P-glycoprotein structural domains determined by thermal unfolding provides insights into its solution structure and function.Biochimica et biophysica acta. Biomembranes · 2017Article
- Rapid enzyme regeneration results in the striking catalytic longevity of an engineered, single species, biocatalytic biofilm.Microbial cell factories · 2016Article
- Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia.Human molecular genetics · 2016Article
- A single residue substitution accounts for the significant difference in thermostability between two isoforms of human cytosolic creatine kinase.Scientific reports · 2016Article
- Streptococcus pneumoniae TIGR4 Flavodoxin: Structural and Biophysical Characterization of a Novel Drug Target.PloS one · 2016Article
- Protein Crystallography in Vaccine Research and Development.International journal of molecular sciences · 2015Review
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Increasing the thermostability of proteins is often crucial for their successful use as analytic, synthetic or therapeutic tools. Most rational thermostabilization strategies were developed on small two-state proteins and, unsurprisingly, they tend to fail when applied to the much more abundant, larger, non-fully cooperative proteins. We show that the key to stabilize the latter is to know the regions of lower stability. To prove it, we have engineered apoflavodoxin, a non-fully cooperative protein on which previous thermostabilizing attempts had failed. We use a step-wise combination of structure-based, rationally-designed, stabilizing mutations confined to the less stable structural region, and obtain variants that, according to their van't Hoff to calorimetric enthalpy ratios, exhibit fully-cooperative thermal unfolding with a melting temperature of 75°C, 32 degrees above the lower melting temperature of the non-cooperative wild type protein. The ideas introduced here may also be useful for the thermostabilization of complex proteins through formulation or using specific stabilizing ligands (e.g. pharmacological chaperones).
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