Protein folding and quality control during nuclear transport.

The spatial separation of protein synthesis from the compartmental destiny of proteins led to the evolution of transport systems that are efficient and yet highly specific. Co-translational transport has emerged as a strategy to avoid cytosolic aggregation of folding intermediates and the need for energy-consuming unfolding strategies to enable transport through narrow conduits connecting compartments. While translation and compartmental translocation are at times tightly coordinated, we know very little about the temporal coordination of translation, protein folding, and nuclear import. Here, we consider the implications of co-translational engagement of nuclear import machinery. We propose that the dynamic interplay of karyopherins and intrinsically disordered nucleoporins create a favorable protein folding environment for cargo en route to the nuclear compartment while maintaining a barrier function of the nuclear pore complex. Our model is discussed in the context of neurological disorders that are tied to defects in nuclear transport and protein quality control.

Electrochemical DNA Biosensor That Detects Early Celiac Disease Autoantibodies.

Although it is estimated that more than one million Americans have celiac disease (CD), it remains challenging to diagnose. CD, an autoimmune and inflammatory response following the ingestion of gluten-containing foods, has symptoms overlapping with other diseases and requires invasive diagnostics. The gold standard for CD diagnosis involves serologic blood tests followed by invasive confirmatory biopsies. Here, we propose a less invasive method using an electrochemical DNA (E-DNA) biosensor for CD-specific autoantibodies (AABs) circulating in blood. In our approach, CD-specific AABs bind a synthetic neoepitope, causing a conformational change in the biosensor, as well as a change in the environment of an attached redox reporter, producing a measurable current reduction. We assessed the biosensor's ability to detect CD-specific patient-derived AABs in physiological buffer as well as buffer supplemented with bovine serum. Our biosensor was able to detect AABs in a dose-dependent manner; increased signal change correlated with increased AAB concentration with an apparent dissociation constant of 0.09 ± 0.03 units/mL of AABs. Furthermore, we found our biosensor to be target-specific, with minimal off-target binding of multiple unrelated biomarkers. Future efforts aimed at increasing sensitivity in complex media may build upon the biosensor design presented here to further improve CD AAB detection and CD diagnostic tools.