34 research outputs found
Smoothing a rugged protein folding landscape by sequence-based redesign
The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation. Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and misfolding. Serpins exist in a metastable state that undergoes a major conformational change in order to inhibit proteases. However, conformational labiality of the native serpin fold renders them susceptible to misfolding, which underlies misfolding diseases such as -antitrypsin deficiency. To investigate how serpins balance function and folding, we used consensus design to create , a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant. Characterization of its structure, folding and dynamics suggest that consensus design has remodeled the folding landscape to reconcile competing requirements for stability and function. This approach may offer general benefits for engineering functional proteins that have risky folding landscapes, including the removal of aggregation-prone intermediates, and modifying scaffolds for use as protein therapeutics.BTP is a Medical Research Council Career Development Fellow. AAN and JJH are supported by the Wellcome Trust (grant number WT 095195). SM acknowledges fellowship support from the Australian Research Council (FT100100960). NAB is an Australian Research Council Future Fellow (110100223). GIW is an Australian Research Council Discovery Outstanding Researcher Award Fellow (DP140100087). AMB is a National Health and Medical Research Senior Research Fellow (1022688). JCW is an NHMRC Senior Principal Research fellow and also acknowledges the support of an ARC Federation Fellowship. We thank the Australian Synchrotron for beam-time and technical assistance. This work was supported by the Multi-modal Australian ScienceS Imaging and Visualisation Environment (MASSIVE) (www.massive.org.au). We acknowledge the Monash Protein Production Unit and Monash Macromolecular Crystallization Facilit
Smoothing a rugged protein folding landscape by sequence-based redesign
The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation.
Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and
misfolding. Serpins exist in a metastable state that undergoes a major conformational change in
order to inhibit proteases. However, conformational labiality of the native serpin fold renders them
susceptible to misfolding, which underlies misfolding diseases such as α1-antitrypsin deficiency. To
investigate how serpins balance function and folding, we used consensus design to create conserpin,
a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant.
Characterization of its structure, folding and dynamics suggest that consensus design has remodeled
the folding landscape to reconcile competing requirements for stability and function. This approach
may offer general benefits for engineering functional proteins that have risky folding landscapes,
including the removal of aggregation-prone intermediates, and modifying scaffolds for use as protein
therapeutics
Em defesa da sociedade: a invenção dos cuidados paliativos e a produção de subjetividades
Benthic macrofauna and the limnological parameters of a first-order stream in Atlantic Forest of Brazilian Northeast
Meiotic behavior of wild Caricaceae species potentially suitable for papaya improvement
Genotyping of gastroenteric viruses in hospitalised children: first report of norovirus GII.21 in Brazil
DECREASING PREVALENCE OF THE ACUTE/SUBACUTE CLINICAL FORM OF PARACOCCIDIOIDOMYCOSIS IN MATO GROSSO DO SUL STATE, BRAZIL
Celiac disease, epilepsy, and cerebral calcifications: A neuropsychological case study
We present the neuropsychological examination of a 6-year-old child with bilateral parietal-occipital calcification associated with celiac disease. The main disruptions were observed in visuo-spatial and visuo-motor organization, spatial analysis and synthesis, as well as visual memory. Other cognitive functions (intelligence, audio-verbal memory, motor functions, and attention) presented no disturbances in the course of the development. The pattern observed in the neuropsychological evaluation is an important indicator of the possible effects of occipital calcification associated with the semiology of occipital lobe epilepsy in the development of cognitive functions, which have not been investigated as yet.Univ Fed Sao Paulo, Child Neurol Sect, Sao Paulo, BrazilUniv Fed Sao Paulo, Child Neurol Sect, Sao Paulo, BrazilWeb of Scienc