Research Interests

Damon Huber is interested in using a combination of biochemistry and molecular genetics to address complex biological problems in bacteria. The research in his lab is focused on the transport of proteins across the cytoplasmic membrane by the Sec machinery in bacteria, protein folding, and the connection between folding and transport.

The main pathway for the transport of proteins across the cytoplasmic membrane in bacteria is the Sec pathway. The research in his lab is currently focused on understanding how the Sec pathway recognizes newly synthesized protein substrates and targets them for transport across the cytoplasmic membrane. Research in the lab combines the relative strengths of biochemistry and bacterial genetics to investigate the mechanistic details of Sec-dependent protein transport in Escherichia coli.

• The mechanism of cotranslational targeting by the “posttranslational” branch of the Sec pathway by SecA. The central component of the Sec pathway is an integral membrane protein complex, SecYEG, which forms a channel in the cytoplasmic membrane through which substrate proteins are transported. There are two main branches of the Sec pathway by which substrate proteins are delivered to SecYEG: the posttranslational branch and the cotranslational branch. The posttranslational branch is responsible for the export of the majority of soluble periplasmic and outer membrane proteins in E. coli. However, until recently very little was known about how substrate proteins were recognized by the posttranslational branch. Export of substrates of the posttranslational branch typically begins either very late in the process of protein synthesis or after synthesis is complete, which has led to the widespread assumption that substrate recognition is independent of protein synthesis. (In contrast, substrates of the cotranslational branch are recognized very early in translation by the SRP, and the ribosome is directly coupled to SecYEG.) However, I recently discovered that a component of the posttranslational Sec machinery, the ATPase SecA, binds to the ribosome and appears to play a role in cotranslationally channeling proteins into the “posttranslational” translocation pathway. My lab is currently investigating the details of the molecular mechanism of substrate recognition by SecA.
• The role of targeting in the folding of substrate proteins in the periplasm. The mechanism of delivery to SecYEG can significantly affect the folding of substrate proteins. For example, several recent studies report that cotranslational export of outer membrane proteins can lead to misfolding and defective assembly into the outer membrane. However, the molecular basis for these differences in folding is still unclear. I am interested in understanding how the mechanism of delivery to SecYEG can affect folding of proteins on the periplasmic side of the cytoplasmic membrane.

Scientific Inspiration

My PhD supervisor, Jon Beckwith. During his long and productive scientific career, Jon used bacterial genetics to study complex biological phenomena ranging from the genetic regulation of the lac operon to protein folding to biogenesis of the bacterial cell envelope. Although we are not exclusively committed to the use of genetics as a research method, genetic thinking lies at the heart of the experimental approach in my lab. In addition, Jon has balanced incredible science with his personal interests and a strong commitment to social justice, which has been an inspiration for me.