BBS Faculty Member - Tom Rapoport

Tom Rapoport

Department of Cell Biology

Harvard Medical School/HHMI
LHRRB, Rm. 613
240 Longwood Avenue
Boston, MA 02115-6091
Tel: 617-432-0637
Fax: 617-432-1190
Lab Members: 13 postdoctoral fellows, 4 graduate students
Visit my lab page here.

We are interested in the molecular mechanisms by which proteins are transported across the endoplasmic reticulum (ER) membrane. Proteins are transported through a protein-conducting channel, formed from a conserved trimeric membrane protein complex, called the Sec61p complex in eukaryotes, and the SecY complex in prokaryotes. The channel is a passive pore that needs to associate with partners that provide a driving force for translocation. We have solved the Xray structure of the resting channel formed from the SecY complex from an archaebacterium and, more recently, the structure of bacterial channels that are “preactivated” by the ATPase SecA. These structures have led to a number of predictions that we are currently testing.

A major direction in the lab is to understand the mechanism of co-translational translocation, in which the ribosome is the major partner. Our present work concentrates on the structure of ribosome- nascent chain-channel complexes. We try to obtain structural information using electron cryo-microscopy (collaboration with the group of Christopher Akey at Boston University), using complexes of non-translating ribosomes and channel. Our current goal is to obtain high-resolution crystal structures of ribosome-channel complexes that contain a translocating polypeptide chain.

Another goal is to understand the mechanism of posttranslational translocation in bacteria, in which the ATPase SecA is the major channel partner. We have obtained crystal structures of a complex containing the channel and SecA, which has led to proposals on the mechanism of translocation. We are currently testing these ideas with biochemical experiments.
We are also interested in the process by which misfolded proteins are transported from the ER back into the cytosol for degradation by the proteasome (a process called ERAD or retro-translocation). Depending on the localization of the misfolded domain of an ER protein, there are three different ERAD pathways, each employing a distinct ubiquitin-ligase complexes. The pathways converge at the point of the p97/Cdc48p ATPase complex, which recognizes ubiquitinated substrates and moves them into the cytosol. Our current efforts are directed towards further elucidation of the molecular mechanism of the ERAD pathways. We are particularly interested in identifying the protein-conducting channel.

A third major project in the lab concerns the mechanism by which the endoplasmic reticulum adopts its characteristic shape. We have used an in vitro assay in Xenopus egg extracts to identify reticulon 4A as a component involved in tubule formation. The reticulons and DP-1/Yop1p appear to shape the tubular ER in all eukaryotic cells. We try to understand the precise mechanism by which these proteins induce tubules. We have identified a class of membrane-bound GTPases that mediate the fusion of ER tubules. We now try to elucidate the mechanism of fusion. Finally, we are interested how the sheets of the ER are generated.

Other project:
Mechanism by which the ER associates with mitochondria.

Last Update: 1/13/2014


For a complete listing of publications click here.



Shibata, Y., Shemesh, T., Prinz, W.A., Palazzo, A.P., Kozlov, M.M., and Rapoport, T.A. (2010) Cell, 143(5), 774-788. Mechanisms determining the morphology of the peripheral ER.

Hu, J., Shibata, Y., Zhu, P.-P., Voss, C., Rismanchi, N., Prinz, W.A., Rapoport, T.A., and Blackstone, C. (2009) Cell 138, 549-561. A class of dynamin-like GTPases involved in the generation of the tubular ER network.

Zimmer, J., Nam, Y., and Rapoport, T.A. (2008) Nature 455, 936-945. Structure of a complex of the ATPase SecA and the protein-translocation channel.

Carvalho, P., Goder, V., and Rapoport T.A. (2006) Cell 126, 361-373. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins.

© 2013 by the President and Fellows of Harvard College