Assistant Professor of Chemistry
email: bakrantz@berkeley.edu
office: 476 Stanley Hall
phone: 510.666.2788
lab: 492 Stanley Hall
lab phone: 510.666.2789
Research Interests
Biophysical chemistry of membrane proteins: molecular mechanisms of how proteins translocate across lipid bilayers, protein unfolding machines, and bacterial membrane transporters.
Research in Professor Krantz's lab centers on the structure/function relationship of channels that translocate proteins across bilayer membranes. This problem's significance stems from the fact that one-half of all proteins produced in a cell must at some point traverse a cellular membrane. Thus a dedicated integral membrane protein complex—or translocase channel—provides the conduit through which the transiting proteins passage. The generality of this problem in biology has meant that many types of translocases have been identified. The present challenge rests on better defining the molecular mechanisms of translocase channels and to establish the broader physical laws that govern transport.
Often, translocase channels contain a central pore too narrow to allow a folded substrate protein to passage, requiring that the protein unfold. His research group is interested in understanding how the substrate proteins unfold and how the unfolded chain reptates (or travels like a snake) through the narrow TC. The latter process adds an entirely new dimension to the current excitement surrounding structure/function studies of ion channels, since a protein polymer is much more than a hydrated metal ion; it is a flexible chain composed of a multitude of functional groups, namely hydrophobic, hydrophilic, cationic and anionic moieties. Numerous questions surround the molecular mechanisms of these translocase machines. Does a translocase channel directly destabilize or unfold its substrate proteins? What drives polypeptide transport? Are the underlying dynamics of the reptating chain best characterized by Brownian-ratchet mechanisms? To address these questions he is investigating translocase channels central to microbial pathogenesis.
Protein translocation is critical to many host-pathogen interactions. Bacteria utilize translocase channels to either secrete toxins and virulence factors or display adhesin molecules on their outermost membranes; and by means of these secreted molecules, the pathogen can successfully attach to, disrupt, and/or invade its host's cells. Anthrax toxin, for example, has proved to be a promising model system to study protein translocation. The toxin is composed of a TC, called protective antigen (PA), which allows its two substrate proteins, lethal and edema factors (LF and EF), to translocate across a host cell's endosomal membrane and enter the cytosol. Once in the cytosol these factors catalyze enzymatic reactions that disrupt the host cell.
Combining biophysical protein folding studies in solution with electrophysiology studies using artificial membrane bilayers, he has been able to develop anthrax toxin into a biophysical system capable of characterizing protein translocation in vitro. Recently, a novel structural feature was identified inside of the PA channel, called the φ clamp; this structure is a lumen-facing, hydrophobic heptad of phenylalanine residues located near the center of the channel. The hydrophobic nature of this φ-clamp site suggests it functions in a chaperone-like capacity and effectively couples the protein unfolding and transport processes. This notion of the channel actively engaging the substrate protein during transport by means of hydrophobic interactions is expected to be a recurring theme in these systems, and understanding the functional consequences of this structural motif will provide key insights into the function of other translocases and unfolding machines in the cell.
Biography
Assistant Professor. Born 1974; B.S., Chemistry, B.A., English, (highest honors) Emory University (1996); Ph.D., Biochemistry & Molecular Biology, University of Chicago (2002) with Tobin Sosnick, studying the biophysics of protein folding; NIH Postdoctoral Fellow (2004-2006) with John Collier, Harvard Medical School, studying the biophysics of anthrax toxin translocation across cell membranes.