Related Experiment Video
Updated: Aug 5, 2026
15:05
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
A domain-swapped proPC1/3 structure reveals a conformational checkpoint for ER export
Pankaj Kumar1,2, Phillip A Hyon1, Rishi Nixon3
1Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Biorxiv : the Preprint Server for Biology
|August 1, 2026
Summary
Prohormone convertase 1/3 (PC1/3) maturation involves a domain-swapped homodimer structure that enables ER exit. This conformational checkpoint, involving a calcium pocket, is crucial for PC1/3 function and explains disease mutations.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Prohormone convertase 1/3 (PC1/3) is essential for producing peptide hormones like insulin.
- PC1/3 is synthesized as a zymogen (proPC1/3) and matures in the endoplasmic reticulum (ER) before secretion.
Purpose of the Study:
- To elucidate the mechanism by which proPC1/3 exits the ER.
- To determine the structure of immature proPC1/3 and its role in ER export.
Main Methods:
- X-ray crystallography was used to determine the structure of an immature, catalytically inactive human proPC1/3 mutant (proPC1/3S382A).
- Analysis of the domain-swapped homodimer conformation and its calcium-binding pocket.
Main Results:
- Immature proPC1/3 exits the ER as a domain-swapped homodimer.
- This domain-swapped conformation completes a calcium pocket, licensing ER exit.
- The calcium pocket acts as a conformational checkpoint for ER export.
Conclusions:
- The study defines a conformational checkpoint for PC1/3 ER export, involving a domain-swapped dimer and a calcium pocket.
- Findings provide insights into PC1/3 maturation and may apply to other PCSK family members.
- The structure explains the impact of various PCSK1 mutations on PC1/3 function.
Related Concept Videos
01:28Protein Translocation Machinery on the ER Membrane
The translocon complex situated on the ER membrane is the main gateway for the protein secretory pathway. It facilitates the transport of nascent peptides into the ER lumen and their insertion into the ER membrane.
Sec61 protein conducting channel
In eukaryotes, the translocon complex comprises a core heterotrimeric translocator channel called the Sec61 complex. This channel includes three transmembrane proteins, Sec61α, Sec61β, and Sec61γ, and is the largest subunit of the translocon complex.
Sec61 protein conducting channel
In eukaryotes, the translocon complex comprises a core heterotrimeric translocator channel called the Sec61 complex. This channel includes three transmembrane proteins, Sec61α, Sec61β, and Sec61γ, and is the largest subunit of the translocon complex.
01:34Directing Proteins to the Rough Endoplasmic Reticulum
The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
01:45ER Retrieval Pathway
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
01:33Coat Assembly and GTPases
Vesicles incorporate different coat protein subunits in different cell locations, which changes the properties of the coat, such as the shape and geometry of the transport vesicles. Thus, vesicle coat proteins also play a significant role in cargo selection.
Coat assembly depends on the local availability of phosphatidylinositol phosphates or PIPs and GTP-binding proteins. Adaptor proteins, which link the coat proteins to the membrane, bind to these PIPs and play a crucial role in controlling...
Coat assembly depends on the local availability of phosphatidylinositol phosphates or PIPs and GTP-binding proteins. Adaptor proteins, which link the coat proteins to the membrane, bind to these PIPs and play a crucial role in controlling...
01:45Tail-anchoring of Proteins in the ER Membrane
Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...
02:04Covalently Linked Protein Regulators
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
These groups modify specific amino acids in a protein.