Molecular Interaction Analysis
Unrivaled Information Content
- Binding Kinetics
- Binding Affinity
- Protein Diameter
- Conformational Change
- Nuclease & Polymerase Activity
- Bispecific Binders & Avidity
- Melting & Thermodynamics
- Multimers & Aggregation
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In the recent work published in Nature, researchers from The Scripps Research Institute report on the novel role that protein ANKRD16 plays in the complex process of protein aggregate-associated neurodegeneration. Vo and Terrey et al demonstrated that in the absence of ANKRD16, neuron loss is induced by the aggregation of proteins mistranslated by tRNA synthetases that carry a mutation in their editing domain. ANKRD16 is found to act as a translational co-factor, contributing to the prevention of mistranslation.
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Using the switchSENSE® technology, the kinetics of binding of ANKRD16 to wild-type, mutated and truncated tRNA synthetase variants were measured. The measurements for the direct binding of ANKRD16 to the different tRNA synthetase variants shed light on the mechanism of ANKRD16 recognition of misactivated amino acid sequences, as well as the location of its binding to the tRNA synthetase, critical to describing ANKRD16’s protective role in neurodegeneration.
Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aarssti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, we identified Ankrd16, a gene that acts epistatically with the Aarsstimutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides. The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.
Paper in JBC 2018
In a recent publication in the Journal of Biological Chemistry, researchers from the MRC Laboratory of Molecular Biology (LMB), show how a low complexity region enhances RNA binding by the YTH domain protein Mmi1, using the switchSENSE® technology.
Taken together, the work reveals how a low-complexity region proximal to a conserved folded domain can adopt an ordered structure to aid nucleic acid binding.
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Mmi1 is an essential RNA-binding protein in the fission yeast Schizosaccharomyces pombe that eliminates meiotic transcripts during normal vegetative growth. Mmi1 contains a YTH domain that binds specific RNA sequences, targeting mRNAs for degradation. The YTH domain of Mmi1 uses a noncanonical RNA-binding surface that includes contacts outside the conserved fold. Here, we report that an N-terminal extension that is proximal to the YTH domain enhances RNA binding. Using X-ray crystallography, NMR and biophysical methods, we show that this low-complexity region becomes more ordered upon RNA binding.
This enhances the affinity of the interaction of the Mmi1 YTH domain with specific RNAs by reducing the dissociation rate of the Mmi1–RNA complex. We propose that the low-complexity region influences RNA binding indirectly by reducing dynamic motions of the RNA binding groove and stabilizing a conformation of the YTH domain that binds to RNA with high affinity. Taken together, our work reveals how a low-complexity region proximal to a conserved folded domain can adopt an ordered structure to aid nucleic acid binding.
Products for High-Performance Analysis
switchSENSE® experiments are performed on reusable multi-electrode, multi-channels biochips.
Fully automated switchSENSE® instruments are 96-well plates compatible and manufactured in Germany.
Including coupling kits, starter packs, training & OQ kits, as well as buffers, solutions and other consumables.
Dr. Michael Schraeml, Head Protein and Enzyme Technologies
ROCHE DIAGNOSTICS GMBH