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Nuclear Protein Sorting01:34

Nuclear Protein Sorting

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Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
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Translocation of proteins across membranes is an ancient process that occurs even in bacteria and archaebacteria. In fact, the components of the translocation machinery are still conserved between prokaryotes and eukaryotes.
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A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
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Eukaryotic cells have different membrane-bound organelles with distinct protein requirements. The process by which proteins are targeted to a specific organelle is called protein sorting.
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Updated: Sep 15, 2025

Purification of the Membrane Compartment for Endoplasmic Reticulum-associated Degradation of Exogenous Antigens in Cross-presentation
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Nucleotide-dependent conformational changes direct peptide export by the transporter associated with antigen

James Lee1, Victor Manon1,2, Jue Chen1,3,4

  • 1Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, NY 10065.

Biorxiv : the Preprint Server for Biology
|July 16, 2025
PubMed
Summary

The transporter associated with antigen processing (TAP) moves peptides into the endoplasmic reticulum for adaptive immunity. Cryo-EM structures reveal its transport cycle, showing how it binds, transports, and releases peptides.

Keywords:
ABC transporterMHC-Iadaptive immunityantigen presentationnucleotide binding domaintransporter associated with antigen processing

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Area of Science:

  • Structural Biology
  • Immunology
  • Molecular Biology

Background:

  • The transporter associated with antigen processing (TAP) is crucial for adaptive immunity by transporting peptides to the endoplasmic reticulum for MHC-I loading.
  • While TAP's peptide-binding selectivity is known, its transport and release mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the structural mechanisms of peptide transport by human TAP.
  • To visualize TAP in multiple functional states throughout its transport cycle.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine high-resolution structures of human TAP.
  • Structures were captured in various functional states, including inward-facing and outward-facing conformations.

Main Results:

  • ATP binding stabilizes the inward-facing conformation of TAP.
  • A temperature-dependent transition to the outward-facing state reconfigures the peptide-binding site for release.
  • ATP hydrolysis and nucleotide-binding domain (NBD) separation reset the transport cycle.

Conclusions:

  • These structures provide a comprehensive framework for understanding TAP's peptide transport mechanism.
  • The findings offer insights into vanadate trapping and trans-inhibition mechanisms.
  • This work clarifies how TAP facilitates peptide loading onto MHC-I molecules.