B.A., Harvard University, 1980
Ph.D., Massachusetts Institute of Technology, 1987
Research Statement
My laboratory is interested in understanding how proteins are targeted to the endoplasmic reticulum (ER) or bacterial cytoplasmic membrane by the signal recognition particle (SRP) and then transported across or integrated into the membrane by the ubiquitous Sec61p/SecY complex. In mammalian cells, SRP recognizes the cleavable signal peptides associated with preproteins and the first transmembrane segment of multi-spanning membrane proteins, which often lack cleavable signal peptides. We have found that in bacteria, SRP recognizes transmembrane segments but not most cleavable signal peptides, and as a consequence most preproteins are targeted to the SecY complex by alternate pathways. We are currently studying the basis for this difference in substrate specificity. We are also investigating the fascinating but poorly understood process by which the Sec61p/SecY complex facilitates the biogenesis of multi-spanning membrane proteins. Finally, we are studying the mechanism by which the expression of SecA, a bacterial-specific ATPase that functions in conjunction with the SecY complex, is regulated at the translational level.
In a separate project we are studying the "autotransporter" or "type V" secretion pathway that is found in many pathogenic Gram-negative bacteria. Autotransporters are proteins that contain two domains, an N-terminal "passenger domain" that often exceeds 100 kD and a 30 kD C-terminal "β domain". After autotransporters are translocated across the cytoplasmic membrane by the SecY complex, the β domain promotes the translocation of its own passenger domain across the outer membrane by an unknown mechanism. The passenger domains of different members of the autotransporter family play various roles in pathogenesis; in some cases they act as adhesins, but in other cases they are cleaved from the cell surface and act as soluble virulence factors. We are currently focusing on elucidating the steps of autotransporter biogenesis and the mechanism of passenger domain translocation across the outer membrane.
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Selected Publications
1. Ieva R, Skillman KM, Bernstein HD Incorporation of a polypeptide segment into the beta-domain pore during the assembly of a bacterial autotransporter. Mol Microbiol(67): 188-201, 2008. [Full Text/Abstract]
2. Barnard TJ, Dautin N, Lukacik P, Bernstein HD, Buchanan SK Autotransporter structure reveals intra-barrel cleavage followed by conformational changes. Nat Struct Mol Biol(14): 1214-20, 2007. [Full Text/Abstract]
3. Dautin N, Barnard TJ, Anderson DE, Bernstein HD Cleavage of a bacterial autotransporter by an evolutionarily convergent autocatalytic mechanism. EMBO J(26): 1942-52, 2007. [Full Text/Abstract]
4. Dautin N, Bernstein HD Protein secretion in gram-negative bacteria via the autotransporter pathway. Annu Rev Microbiol(61): 89-112, 2007. [Full Text/Abstract]
5. Hegde RS, Bernstein HD The surprising complexity of signal sequences. Trends Biochem Sci(31): 563-71, 2006. [Full Text/Abstract]
6. Woolhead CA, Johnson AE, Bernstein HD Translation arrest requires two-way communication between a nascent polypeptide and the ribosome. Mol Cell(22): 587-98, 2006. [Full Text/Abstract]
7. Szabady RL, Peterson JH, Skillman KM, Bernstein HD An unusual signal peptide facilitates late steps in the biogenesis of a bacterial autotransporter. Proc Natl Acad Sci U S A (102): 221-6, 2005. [Full Text/Abstract]
8. Skillman KM, Barnard TJ, Peterson JH, Ghirlando R, Bernstein HD Efficient secretion of a folded protein domain by a monomeric bacterial autotransporter. Mol Microbiol(58): 945-58, 2005. [Full Text/Abstract]
9. Peterson JH, Woolhead CA, Bernstein HD Basic amino acids in a distinct subset of signal peptides promote interaction with the signal recognition particle. J Biol Chem (278): 46155-62, 2003. [Full Text/Abstract]
10. Lu Y, Qi HY, Hyndman JB, Ulbrandt ND, Teplyakov A, Tomasevic N, Bernstein HD Evidence for a novel GTPase priming step in the SRP protein targeting pathway. EMBO J (20): 6724-34, 2001. [Full Text/Abstract]
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