Nature study co-led by Institute professor sheds new light on process blood clotting, immune response
Feb. 21—Bin Liu, PhD, associate professor at The Hormel Institute, University of Minnesota, is among the authors of a newly published paper appearing in the leading scientific journal Nature, entitled "Molecular basis of vitamin K driven γ-carboxylation at membrane interface."
The study, co-led by Dr. Weikai Li, PhD (Washington University, St. Louis, Missouri) and Dr. Liu, sheds new light on mechanisms involved with a process called γ-carboxylation and has implications for better understanding and treating hemostatic and non-hemostatic disorders.
When you scrape your knee on the sidewalk, your body has to react quickly to stop the bleeding and protect you from infection. This complex response involves multi-step processes, starting with the formation of a blood clot, a process known as hemostasis. Hemostasis alone is a complex process that involves a number of highly orchestrated steps at the cellular level. One of the steps in hemostasis is known as γ-carboxylation (gamma carboxylation) — and the findings from this study offer new observations related to the process.
Certain coagulation and anticoagulation proteins — proteins that aid or prevent blood clotting — have structural features rich in the amino acid glutamate. The enzyme vitamin K-dependent γ-carboxylase (VKGC) modifies these glutamates into γ-carboxyglutamyl (Gla) residues. From there, assisted by calcium ions, protein complexes are assembled that are crucial in carrying out a series of biochemical reactions allowing processes like hemostasis to take place.
But hemostasis is only one crucial bodily process tied to γ-carboxylation. It is also significant for functions, such as inhibiting thrombosis (when blood clots block blood flow in vessels), calcium homeostasis (maintaining stable levels of calcium ions), immune response, and endocrine regulation.
When γ-carboxylation isn't carried out properly, serious health problems can occur. Mutations in hemostatic proteins can interfere with γ-carboxylation and can cause hemophilia B, thrombophilia, and other bleeding complications. Deficient γ-carboxylation of certain proteins can lead to bone disorders and vascular calcification, which is connected to atherosclerosis and chronic kidney diseases. This makes the mechanisms surrounding γ-carboxylation a possible target for treating or preventing a vast array of related conditions.
"We believe our findings will be of interest to a very broad audience, including scientists studying integral membrane enzymes, membrane biologists and structural biologists, cardiovascular biologists, hematologists, and pharmacologists, as well as clinical researchers and physicians," Liu.
With the goal of better understanding the unique biochemistry, and using The Hormel Institute's cryogenic-sample electron microscopy (cryoEM) facilities, the team of researchers mapped seven cryoEM structures for analysis. These included VKGC in its unbound form, as well as in complex with the Prop-Glu of proteins that included factor IX (FIX), factor (FX), protein C, and transmembrane Gla protein 2 (TMG2) — each in different carboxylation states, as well as with and without KH2 .
Representing a significant breakthrough for the field of membrane enzymology, these structures and supporting functional analyses reveal the mechanisms underlying multiple substrate specificity, coupling of epoxidation with carboxylation, and allosteric motions during VKGC catalysis.
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