Extracting multi-state information from complex biological sensors.

The Krantz laboratory is interested broadly in the basic science and biophysical chemistry of membrane proteins involved in cellular transport and signaling.

The laboratory’s core strength lies in its ability to extract multi-state information from complex biological sensors. By utilizing the anthrax toxin nanopore as a dynamic biological machine rather than a static pore, the team is paving the way for true single-molecule proteomics and label-free peptide sequencing.

Beyond structural engineering, the lab is mapping evolutionary metabolic ketone/lactate sensors in psychiatric and neurodegenerative diseases as well as resolving the apical receptor paradox of intestinal anthrax via bile acid sensing. Most recently, meta-genomic and transcriptomic analyses identified the shared catastrophic thermodynamic failures of the brain’s GPCR HCAR metabolic sensor array in severe psychiatric (Schizophrenia) and neuro-inflammatory (Multiple Sclerosis) conditions.

Core Research Pillars

Transmembrane Protein Translocation

Elucidating the mechanism of protein translocation using model systems, such as anthrax toxin, will: broaden our basic understanding of protein transport across membranes, further countermeasure development, and allow the toxin to be adapted as a means for targeted protein and small-molecule drug delivery. The laboratory is currently using single-channel electrophysiology and structural studies to understand how a series of polypeptide clamp structures work cooperatively to promote efficient unfolding and translocation.

Nanopore Biosensing

Working toward deeper insight on the structure and function of the anthrax toxin nanopore, and other similar systems, will ultimately enable the creation of a multiplexed sensor array, or bioelectronic nose, capable of detecting toxic analytes and peptides in clinical samples, key industrial processes, the food supply, and the environment. Advanced computational methods (Deep Learning and Machine Learning) are being used to process large datasets and classify samples.

Nanopore Peptide Sequencing

We are investigating the feasibility of Deep Learning-enabled nanopore protein sequencing. Using protein engineering and advanced deep learning methods, we will identify and interpret amino acid-specific signatures within real multi-state polypeptide translocation events, establishing the experimental and computational foundation for nanopore protein sequencing.

Bile Acid & Allosteric Sensing

Structure/function work is resolving the apical receptor paradox of intestinal anthrax via a novel mechanism of bile acid sensing. X-ray structures and docking models show binding of bile acids to sites joining the receptor binding domain to the pore-forming domain. This enables the loosening of the structure to form pores even at normal physiological neutral pH conditions of the gut, allowing for apical insertion into membranes without receptor-mediated endocytosis and typical acidification.

Capsule & Toxin Co-complexes

Pathogenic strains of Bacillus anthracis secrete a poly-glutamic acid virulence factor consisting of long, linear polypeptides of D-Glu polymerized via amide linkages. These polymers, which can be cleaved into smaller polypeptides, can bind to all three anthrax toxin subunits. We want to better understand how these co-complexes guide anthrax toxin assembly and re-direct the toxin during trafficking into the host cell.

Metabolic Psychiatry & Neuroimmunology

Meta-genomic and transcriptomic analyses identified shared catastrophic thermodynamic failures of the brain’s GPCR HCAR1/2/3 metabolic sensor array on chromosome 12 in severe psychiatric (Schizophrenia) and neuro-inflammatory (Multiple Sclerosis) conditions. These studies explain how ketogenic diets can alleviate Schizophrenia due to downregulated HCAR2 ketone sensor transcription, and how HCAR1 downregulation in MS renders immune cells "lactate blind," driving hyperproliferation and pathogenesis.