PXD058943-1

PXD058943 is an original dataset announced via ProteomeXchange.

Title	A multiple myeloma-associated mutation unravels a mechanism of oligomerization-mediated product inhibition in GGPPS
Description	Protein prenylation regulates the cellular localization of small GTPases and is pivotal for multiple myeloma (MM) pathology. Geranylgeranyl diphosphate synthase (GGPPS), synthesizing a prenylation moiety, exhibits dimeric or hexameric stoichiometry in different species. However, the functional significance of this divergence remains elusive. Focusing on the hexameric human paralog, formed by trimer-of-dimers, we uncover that GGPPSR235C, expressed in an MM cell line, localizes to the active site lid region at the inter-dimeric interface. Using crystallography and mass spectrometry (MS), we show that GGPPSR235C retains its hexameric stoichiometry but exhibits destabilized inter-dimer interactions. Unexpectedly, this results in increased apparent substrate affinity and product release kinetics. These functional effects are further enhanced in a dimeric mutant, GGPPSY246D. Combining MS and fluorescence spectroscopy, we exposed that reduced lid dynamics and increased active site occupancy by the product are intertwined. Together, our results expose product inhibition as a regulatory mechanism in GGPPS, driven by hexamerization.
HostingRepository	PRIDE
AnnounceDate	2025-07-08
AnnouncementXML	Submission_2025-07-08_00:45:06.091.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jasmína Portašiková
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro; SYNAPT G2-Si

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-17 07:18:27	ID requested
⏵ 1	2025-07-08 00:45:06	announced

10.1111/FEBS.70181;

submitter keyword: native MS, HDX-MS,prenyltransferase, geranylgeranyl diphosphate synthase

Petr Man
contact affiliation	Institute of Microbiology - BioCeV, Academy of Sciences of the Czech Republic
contact email	pman@biomed.cas.cz
lab head
Jasmína Portašiková
contact affiliation	Charles University, Faculty of Science, Prague, Czech Republic
contact email	portasij@natur.cuni.cz
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/2025/07/PXD058943

PRIDE project URI

• PRIDE
  1. PXD058943
     1. Label: PRIDE project
     2. Name: A multiple myeloma-associated mutation unravels a mechanism of oligomerization-mediated product inhibition in GGPPS