We are interested in questions related to membrane protein biogenesis, structure, and function. Membrane proteins represent a unique and significant portion of the proteome (20-30%) and they mediate numerous processes essential to life.

Biosynthetically, structurally and functionally, membrane proteins must follow interesting, dedicated principles. For example, unlike soluble proteins, most membrane proteins are translated by membrane-bound ribosomes and then assemble and function inside the lipophilic environment of the membrane.

We ask how cells produce membrane proteins and how various structural determinants affect their function: (i) How ribosomes and mRNAs target the membrane, where localized translation of membrane proteins occurs. (ii) What dictates the fascinating capabilities of multidrug transporters and the multidrug-efflux phenomenon.

Biogenesis of membrane proteins: Surprises in vivo

Biogenesis of membrane proteins: Surprises in vivo

All living cells utilize conserved systems responsible for membrane protein biogenesis, including the signal recognition particle (SRP) and its receptor.

The SRP system contains a membrane-bound SRP-receptor and an SRP protein-RNA complex, which recognizes nascent hydrophobic peptides in the process of translation. Whereas the SRP pathway has been elucidated mainly through a remarkable series of in vitro studies, we study major aspects of the pathway in vivo.

Our results were both surprising and unpredicted. Together, these studies support an alternative order of events in the E. coli targeting pathway. Our model predicts that (i) The SRP receptor is able to deliver ribosomes to the membrane during its own translation; (ii) mRNAs of membrane proteins might be targeted to membrane associated ribosomes, independently of translation; and (iii) the SRP functions downstream of the SRP-receptor. This hypothesis is currently being further investigated in our lab.

Multidrug efflux: Intriguing mechanistic concepts

Multidrug efflux: Intriguing mechanistic concepts

The efflux of multiple drugs by Mdr transporters represents a major obstacle to successfully treating cancer and infectious diseases.

In addition to their clinical importance, Mdr transporters attracted us because they have intriguing mechanistic characteristics that differ substantially from those of substrate-specific transport systems.

Our studies of the E. coli Mdr transporter MdfA demonstrated that in order for these transporters to function in multidrug resistance, they must be exceptionally flexible in structure and function. As major goals for the future, we hope to elucidate critical structural and functional aspects of multidrug efflux by MdfA.