PXD010334 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation. |
Description | Allosteric regulation is central to the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in cancer metabolism. Multiple activating and inhibitory allosteric ligands regulate PKM2 activity by controlling the equilibrium between high activity tetramers and low activity dimers and monomers. However, how allosteric inputs from simultaneous binding of different ligands are integrated to regulate PKM2 activity remains elusive. Here, we show that, [PKM2 activation and tetramerisation can be uncoupled as] in the presence of the allosteric inhibitor phenylalanine (Phe), saturating amounts of the activator fructose 1,6-bisphosphate (F-1,6-bP) can induce PKM2 tetramerisation, but fail to maximally increase enzymatic activity. We use a new computational framework to identify residues that mediate FBP-induced allostery and show that, while mutation of A327 and C358 do not abrogate the ability of F-1,6-BP to increase PKM2 activity, it prevents Phe from interfering with it. Our findings demonstrate a role for residues involved in FBP allostery in enabling the integration of allosteric input from Phe and reveal an allosteric cross-talk that underlies the co-ordinate regulation of PKM2 activity by distinct allosteric ligands. The absolute amount of the isoforms of PKM (PKM1/2) were quantified in the cell lines of interested to inform the described model. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_04:46:21.929.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Vesela Encheva |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | iodoacetamide derivatized residue |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2018-07-06 06:53:14 | ID requested | |
1 | 2019-11-12 12:05:16 | announced | |
⏵ 2 | 2024-10-22 04:46:30 | announced | 2024-10-22: Updated project metadata. |
Publication List
10.7554/eLife.45068; |
Macpherson JA, Theisen A, Masino L, Fets L, Driscoll PC, Encheva V, Snijders AP, Martin SR, Kleinjung J, Barran PE, Fraternali F, Anastasiou D, Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation. Elife, 8():(2019) [pubmed] |
Keyword List
curator keyword: Biological |
submitter keyword: SRM, PRM,PKM2, quantitation, QExactive |
Contact List
Bram Snijders |
contact affiliation | Head of the Crick Mass Spectrometry Proteomics Platform The Francis Crick Institute 1 Midland Road London NW1 1AT |
contact email | Bram.Snijders@crick.ac.uk |
lab head | |
Vesela Encheva |
contact affiliation | The Francis Crick Institute |
contact email | Vesela.Encheva@crick.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD010334
- Label: PRIDE project
- Name: Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation.