PXD052939

PXD052939 is an original dataset announced via ProteomeXchange.

Title	Structural mechanism of γ-carboxylation coupled to vitamin K epoxidation at membrane interface
Description	Hemostasis and various non-hemostatic physiologies require γ-carboxylation of designated glutamates in vitamin K-dependent proteins (VKDPs), a process coupled with epoxidation of vitamin K hydroquinone (KH2) by membrane-integrated γ-carboxylase (VKGC). To understand this unique biochemistry, we determined cryo-electron microscopy structures of human VKGC in unbound form, with KH2 and four VKDPs possessing propeptides and glutamate-rich domains in different carboxylation states. VKGC recognizes propeptides via knob-and-hole interactions and adaptively binds tethered glutamate-containing segments. Propeptide binding allosterically triggers KH2 epoxidation, from which successive reactions generate a hydroxide superbase that deprotonates γ-carbon of a glutamate positioned by hydrogen bonding. A sealed hydrophobic tunnel protects and guides superbase diffusion to reach this carboxylation site across membrane interface. These structural insights and functional findings advance membrane enzymology and inspire anticoagulation therapies.
HostingRepository	PRIDE
AnnounceDate	2025-12-22
AnnouncementXML	Submission_2025-12-21_16:07:51.683.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Aaron Ammerman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	carboxylated residue; monohydroxylated residue; iodoacetic acid derivatized residue
Instrument	timsTOF Pro 2; Orbitrap Ascend

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-07 17:08:58	ID requested
⏵ 1	2025-12-21 16:07:54	announced

10.1038/s41586-025-08648-1;

Cao Q, Ammerman A, Saimi M, Lin Z, Shen G, Chen H, Sun J, Chai M, Liu S, Hsu FF, Krezel AM, Gross ML, Xu J, Garcia BA, Liu B, Li W, -carboxylation at the membrane interface. Nature, 639(8055):816-824(2025) [pubmed]

submitter keyword: Factor IX, vitamin K epoxide, VKGC, FIX,γ-carboxylation, TMG2

Weikai Li
contact affiliation	Department of Biochemistry Biophysics and Structural Biology, Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri, United States
contact email	weikai@wustl.edu
lab head
Aaron Ammerman
contact affiliation	Washington University in St. Louis - Li Lab
contact email	a.ammerman@wustl.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/12/PXD052939

PRIDE project URI

• PRIDE
  1. PXD052939
     1. Label: PRIDE project
     2. Name: Structural mechanism of γ-carboxylation coupled to vitamin K epoxidation at membrane interface