Related Experiment Video

Updated: Oct 13, 2026

A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
09:37

A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging

Published on: July 14, 2016

Secretion, gamma-carboxylation, and endoplasmic reticulum-associated degradation of chimeras with mutually exchanged

F Tokunaga1, S Takeuchi, S Omura

  • 1Department of Life Science, Faculty of Science, Himeji Institute of Technology, Harima Science Garden City, Hyogo, Japan.

Thrombosis Research
|September 6, 2000
PubMed

Insights

Warfarin sensitivity in vitamin K-dependent factors like prothrombin and protein C is complex. Protein C is more susceptible to warfarin-induced degradation due to its overall structure, not just the Gla domain.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Warfarin, a vitamin K antagonist, reduces vitamin K-dependent coagulation factors.
  • Different factors exhibit varying sensitivity to warfarin, despite sharing Gla domains.

Purpose of the Study:

  • Investigate structural elements influencing warfarin sensitivity of prothrombin and protein C.
  • Determine the role of Gla domains and overall protein structure in warfarin-induced degradation.

Main Methods:

  • Expression of chimeric proteins (prothrombin with protein C domains, protein C with prothrombin domains) in cell lines (HepG2, BHK).
  • Analysis of protein secretion, gamma-carboxylation, and intracellular degradation pathways (proteasome, ER-associated degradation).

Main Results:

  • Chimeric prothrombin (with protein C's Gla domain) retained prothrombin's warfarin sensitivity, indicating the Gla domain alone doesn't dictate protein C's sensitivity.
  • Chimeric protein Cs (with prothrombin's Gla domain or prepropeptide/Gla domain) showed impaired secretion and intracellular degradation, despite normal gamma-carboxylation.
  • Warfarin-induced degradation is linked to the overall structure and conformation of these proteins.

Conclusions:

  • The Gla domain is insufficient to explain differential warfarin sensitivity.
  • Protein C's susceptibility to warfarin-induced ER-associated degradation involves its entire structure and conformation, impacting quality control mechanisms.

More Related Videos

Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase11:57

Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase

Published on: June 24, 2025

The Development and Application of Biophysical Assays for Evaluating Ternary Complex Formation Induced by Proteolysis Targeting Chimeras (PROTACS)07:22

The Development and Application of Biophysical Assays for Evaluating Ternary Complex Formation Induced by Proteolysis Targeting Chimeras (PROTACS)

Published on: January 12, 2024

Related Concept Videos

Protein Folding Quality Check in the RER01:29

Protein Folding Quality Check in the RER

ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
Protein Modifications in the RER01:26

Protein Modifications in the RER

Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal sequences.
Protein Complexes with Interchangeable Parts01:57

Protein Complexes with Interchangeable Parts

Groups of proteins may form a complex where each protein in this complex has a different role in the overall execution of the complex’s function. Often some of the proteins in the complex can be replaced by a closely related variant to give a complex that contains many of the same components yet is functionally distinct.
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order to...
Coat Assembly and GTPases01:33

Coat 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...
Proteins: From Genes to Degradation02:11

Proteins: From Genes to Degradation

Within a biological system, the DNA encodes the RNA, and the nucleotide sequence in the RNA further defines the amino acid sequence in the protein. This is referred to as “The Central Dogma of Molecular Biology” - a term coined by Francis Crick.  Central dogma is a firm principle in biology that defines the flow of genetic information within any life form. The two fundamental steps in central dogma are - transcription and translation.
Transcription is the synthesis of RNA molecules by RNA...