Maurice Montal

Research

The key scientific question has been how membrane proteins function in terms of the underlying structure. These entities are truly smart materials. Proteins are nanomachines and marvels of protein chemistry. Lipid bilayers, the basic structural elements of biological membranes, are nanodevices which exploit self-assembly principles to provide the exquisite environment for proteins to operate. Together as a system, proteins embedded within lipid bilayers, embody the basis for biosensor and nanosensor technology. They also emerge as templates for molecular mimicry and design and follow the hierarchical organization underpinning complex systems. Our programs are of prime significance to health science and biodefense; they also comprise components of relevance to the pharmaceutical and cosmeceutical industries.

Specifically, our aim is to understand the structures and the mechanisms underlying nerve cell function and dysfunction. We are interested in the molecular basis of the intrinsic excitability of neurons, the communication of excitability between neurons, neuronal cell survival and death, the processes leading to neurodegeneration, and the genetic components in the pathogenesis of some forms of infant epilepsy. Given that our subjects of inquiry are ion-conducting and protein-conducting channels, key elements of the nerve cell, they embody drug targets; therefore, our programs encompass a component directed to screen or discover agents that impact these processes and, may in due turn, become clinically important drugs.

Botulinum neurotoxin (BoNT) is considered the most potent toxin; it is the causative agent of botulism, a neuroparalytic illness, and a major bioweapon without an antidote. A research program is directed towards this goal. Our objective is to understand the intricacies of intracellular trafficking of BoNT that may disclose novel pathways to escort, target, and insert it into membranes. This information may prove diagnostic in identifying unsuspected sites for intervention and plausible strategies for targeted drug delivery. BoNT is a modular nanomachine in which one of its modules -- the heavy chain channel -- operates as a specific protein translocating transmembrane chaperone for another of its component modules -- the light chain protease. We investigate the dynamics of protein-translocation in neuronal cells focusing on the interactions between the channel/chaperone and its cargo using an assay with single molecule sensitivity. This strategy led us to uncover an entirely unknown succession of intermediate states during translocation of the cargo which reveal transient protein-protein interactions occurring at distinct stages during protease translocation through the channel.

Another major area of interest concerns the design of biosensors based on lipid bilayers membranes containing a number of designed channel proteins that emulate those naturally occurring in the brain. Such devices are indeed nanomachines which may display unparalleled sensitivity in analyte detection, including but not limited to biological and environmental toxins, and also in sensing physical stimuli such as light, temperature, pressure or electric fields.