Tom A Rapoport
Harvard University, MA·Biochemistry
Cells are packed with membrane-bound compartments, and many proteins must cross a membrane to reach the right place or to be destroyed. How these large molecules get through an oily barrier is a basic question in cell biology.
- Fields
Biochemistry
Biophysics
Biology
- Topics
protein translocation
endoplasmic reticulum
ER-associated degradation
- Grants
- 1 known grant, through May 2027
What they work on
- Determine how misfolded glycoproteins, proteins carrying sugar chains, are delivered to the Hrd1 complex and moved from the ER interior across the membrane, building on cryo-electron microscopy structures.
- Determine how the Cdc48 motor protein pulls ERAD substrates into the cytosol, and test whether membrane proteins are extracted together with bound lipids.
- Investigate how shuttling factors and Cdc48-binding cofactors hand substrates from Cdc48 to the 26S proteasome, the cell's main protein-degrading machine.
- Test whether Pex13 forms a nuclear pore-like structure through which cargo-bound receptors cross the peroxisomal membrane during protein import.
- Test whether a ubiquitin ligase complex forms a channel that recycles import receptors back to the cytosol, by reconstituting ubiquitination and Pex1/Pex6 extraction with purified proteins.
More about the research
It also matters for medicine: when proteins in the endoplasmic reticulum (ER), the cell's main protein-folding compartment, fold incorrectly, they are pulled back out and degraded. That degradation causes diseases such as cystic fibrosis. Faulty import of proteins into peroxisomes, small compartments that handle certain fats and other molecules, causes disorders like Zellweger syndrome. This project seeks a mechanistic, step-by-step explanation of both pathways.
Why it matters
Many diseases, including cystic fibrosis and α1-antitrypsin deficiency, arise when ER proteins misfold and are degraded, and some viruses and toxins hijack this degradation pathway. A clearer picture of how proteins cross membranes could explain these diseases and could point to drugs that selectively block the pathway. The work may also improve understanding and treatment of peroxisomal disorders such as Zellweger syndrome.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Malavika Raman
Tufts University, MA·Biochemistry
Identify how UBXN1 represses translation (protein synthesis at the ribosome), testing whether it binds specific ribosomal proteins in a ubiquitin-dependent way.
Stephanie Gates
University of Missouri-Columbia, MO·Biochemistry
Dissect how the Hsp70/CHIP/BAG-1 chaperone complex affects each step of proteasomal degradation, including ubiquitin tagging, substrate binding and breakdown, using in vitro assays with purified proteins.
Smriti Sangwan
Northwestern University, IL·Biochemistry·Early-career
Determine how IRE1, an ER stress sensor, physically connects to the protein-making translational machinery, using single-particle cryo-electron microscopy to resolve the 3D structures involved.
The school
Harvard University: 42 labs on PI Pages, $1.5B a year on research, 712 research doctorates a year.
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