Photo of Tom A. Rapoport,  PhD

Tom A. Rapoport, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-0637
Fax: (617) 432-1190


tom_rapoport@hms.harvard.edu

Tom A. Rapoport, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Professor, Cell Biology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

The lab is interested in how proteins cross membranes. We have determined the X-ray structures of the protein-conducting SecY/Sec61 channel that allows proteins to move from the cytosol across the membrane or to integrate into it. We have also determined a crystal structure of the SecY channel in complex with the SecA ATPase that pushes polypeptides through the channel. We are now using the structures to address the mechanism of protein translocation in more detail. Another project in the lab concerns the mechanism by which misfolded ER proteins are transported back into the cytosol and degraded by the proteasome (ERAD or retro-translocation). Finally, we are interested in the mechanisms by which the ER achieves its characteristic morphologies. We have identified proteins that shape tubules and sheets, fuse ER membranes, and generate tubular junctions. All these projects have a high relevance to cancer research. For example, our research addresses how growth factors are secreted from cells and how tyrosine kinases are integrated into membranes.

Publications

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  • Chen Y, Bauer BW, Rapoport TA, Gumbart JC. Conformational Changes of the Clamp of the Protein Translocation ATPase SecA. J Mol Biol 2015; 427:2348-59. PubMed
  • Blok NB, Tan D, Wang RY, Penczek PA, Baker D, DiMaio F, Rapoport TA, Walz T. Unique double-ring structure of the peroxisomal Pex1/Pex6 ATPase complex revealed by cryo-electron microscopy. Proc Natl Acad Sci U S A 2015. PubMed
  • Junne T, Wong J, Studer C, Aust T, Bauer BW, Beibel M, Bhullar B, Bruccoleri R, Eichenberger J, Estoppey D, Hartmann N, Knapp B, Krastel P, Melin N, Oakeley EJ, Oberer L, Riedl R, Roma G, Schuierer S, Petersen F, Tallarico JA, Rapoport TA, Spiess M, Hoepfner D. Decatransin, a new natural product inhibiting protein translocation at the Sec61/SecYEG translocon. J Cell Sci 2015; 128:1217-29. PubMed
  • Stein A, Ruggiano A, Carvalho P, Rapoport TA. Key Steps in ERAD of Luminal ER Proteins Reconstituted with Purified Components. Cell 2014; 158:1375-88. PubMed
  • Bauer BW, Shemesh T, Chen Y, Rapoport TA. A "Push and Slide" Mechanism Allows Sequence-Insensitive Translocation of Secretory Proteins by the SecA ATPase. Cell 2014; 157:1416-29. PubMed
  • Park E, Rapoport TA. Bacterial protein translocation requires only one copy of the SecY complex in vivo. J Cell Biol 2012; 198:881-93. PubMed
  • Liu TY, Bian X, Sun S, Hu X, Klemm RW, Prinz WA, Rapoport TA, Hu J. Lipid interaction of the C terminus and association of the transmembrane segments facilitate atlastin-mediated homotypic endoplasmic reticulum fusion. Proc Natl Acad Sci U S A 2012; 109:E2146-54. PubMed
  • Bian X, Klemm RW, Liu TY, Zhang M, Sun S, Sui X, Liu X, Rapoport TA, Hu J. Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes. Proc Natl Acad Sci U S A 2011; 108:3976-81. PubMed
  • Chen X, Tukachinsky H, Huang CH, Jao C, Chu YR, Tang HY, Mueller B, Schulman S, Rapoport TA, Salic A. Processing and turnover of the Hedgehog protein in the endoplasmic reticulum. J Cell Biol 2011; 192:825-38. PubMed
  • Shibata Y, Shemesh T, Prinz WA, Palazzo AF, Kozlov MM, Rapoport TA. Mechanisms determining the morphology of the peripheral ER. Cell 2010; 143:774-88. PubMed
  • Rapoport TA. A preliminary report on my life in science. Mol Biol Cell 2010; 21:3770-2. PubMed
  • Carvalho P, Stanley AM, Rapoport TA. Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p. Cell 2010; 143:579-91. PubMed
  • Schulman S, Wang B, Li W, Rapoport TA. Vitamin K epoxide reductase prefers ER membrane-anchored thioredoxin-like redox partners. Proc Natl Acad Sci U S A 2010; 107:15027-32. PubMed
  • Li W, Schulman S, Dutton RJ, Boyd D, Beckwith J, Rapoport TA. Structure of a bacterial homologue of vitamin K epoxide reductase. Nature 2010; 463:507-12. PubMed
  • Zimmer J, Rapoport TA. Conformational flexibility and peptide interaction of the translocation ATPase SecA. J Mol Biol 2009; 394:606-12. PubMed
  • Bauer BW, Rapoport TA. Mapping polypeptide interactions of the SecA ATPase during translocation. Proc Natl Acad Sci U S A 2010; 106:20800-5. PubMed
  • Hu J, Shibata Y, Zhu PP, Voss C, Rismanchi N, Prinz WA, Rapoport TA, Blackstone C. A class of dynamin-like GTPases involved in the generation of the tubular ER network. Cell 2009; 138:549-61. PubMed
  • Rapoport TA. Membrane Shape. Annu Rev Cell Dev Biol 2009; 25:329-54. PubMed
  • Zimmer J,Nam Y,Rapoport TA. Structure of a complex of the ATPase SecA and the protein-translocation channel. Nature 2008; 455:936-43. PubMed
  • Erlandson KJ,Miller SB,Nam Y,Osborne AR,Zimmer J,Rapoport TA. A role for the two-helix finger of the SecA ATPase in protein translocation. Nature 2008; 455:984-7. PubMed
  • Rapoport TA. Protein transport across the endoplasmic reticulum membrane. FEBS J 2008; 275:4471-8. PubMed
  • Shibata Y, Voss C, Rist JM, Hu J, Rapoport TA, Prinz WA, Voeltz GK. The reticulon and DP1/Yop1p proteins form immobile oligomers in the tubular endoplasmic reticulum. J Biol Chem 2008; 283:18892-904. PubMed
  • Menetret JF,Hegde RS,Aguiar M,Gygi SP,Park E,Rapoport TA,Akey CW. Single copies of Sec61 and TRAP associate with a nontranslating mammalian ribosome. Structure 2008; 16:1126-37. PubMed
  • Erlandson KJ, Or E, Osborne AR, Rapoport TA. Analysis of polypeptide movement in the SecY channel during SecA-mediated protein translocation. J Biol Chem 2008; 283:15709-15. PubMed
  • Goder V, Carvalho P, Rapoport TA. The ER-associated degradation component Der1p and its homolog Dfm1p are contained in complexes with distinct cofactors of the ATPase Cdc48p. FEBS Lett 2008; 582:1575-80. PubMed
  • Hu J, Shibata Y, Voss C, Shemesh T, Li Z, Coughlin M, Kozlov MM, Rapoport TA, Prinz WA. Membrane proteins of the endoplasmic reticulum induce high-curvature tubules. Science 2008; 319:1247-50. PubMed
  • Menetret JF, Schaletzky J, Clemons WM Jr, Osborne AR, Skanland SS, Denison C, Gygi SP, Kirkpatrick DS, Park E, Ludtke SJ, Rapoport TA, Akey CW. Ribosome binding of a single copy of the SecY complex: implications for protein translocation. Mol Cell 2007; 28:1083-92. PubMed
  • Burton BM, Marquis KA, Sullivan NL, Rapoport TA, Rudner DZ. The ATPase SpoIIIE transports DNA across fused septal membranes during sporulation in Bacillus subtilis. Cell 2007; 131:1301-12. PubMed
  • Palazzo AF, Springer M, Shibata Y, Lee CS, Dias AP, Rapoport TA. The signal sequence coding region promotes nuclear export of mRNA. PLoS Biol 2007; 5:e322. PubMed
  • Ye J, Cho SH, Fuselier J, Li W, Beckwith J, Rapoport TA. Crystal structure of an unusual thioredoxin protein with a zinc finger domain. J Biol Chem 2007; 282:34945-51. PubMed
  • Rapoport TA. Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. Nature 2007; 450:663-9. PubMed
  • Or E, Rapoport T. Cross-linked SecA dimers are not functional in protein translocation. FEBS Lett 2007; 581:2616-20. PubMed
  • Carvalho P, Goder V, Rapoport TA. Distinct Ubiquitin-Ligase Complexes Define Convergent Pathways for the Degradation of ER Proteins. Cell 2006; 126:361-73. PubMed
  • Ye J, Osborne AR, Groll M, Rapoport TA. RecA-like motor ATPases--lessons from structures. Biochim Biophys Acta 2004; 1659:1-18. PubMed
  • Rapoport TA, Goder V, Heinrich SU, Matlack KE. Membrane-protein integration and the role of the translocation channel. Trends Cell Biol 2004; 14:568-75. PubMed
  • Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 2004; 429:841-7. PubMed
  • Van den Berg B, Clemons WM, Collinson I, Modis Y, Hartmann E, Harrison SC, Rapoport TA. X-ray structure of a protein-conducting channel. Nature 2003; 427:36-44. PubMed
  • Tsai B, Gilbert JM, Stehle T, Lencer W, Benjamin TL, Rapoport TA. Gangliosides are receptors for murine polyoma virus and SV40. EMBO J 2003; 22:4346-55. PubMed
  • Heinrich SU, Rapoport TA. Cooperation of transmembrane segments during the integration of a double-spanning protein into the ER membrane. EMBO J 2003; 22:3654-63. PubMed
  • Ye Y, Meyer HH, Rapoport TA. Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J Cell Biol 2003; 162:71-84. PubMed
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