PXD031928-1

PXD031928 is an original dataset announced via ProteomeXchange.

Title	Multi-omics analysis of MEN1 missense mutations identifies disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity
Description	Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes in the nucleus. We identified three missense mutations, R52G, E255K and E359K, which display predominant reduction in interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions.
HostingRepository	PRIDE
AnnounceDate	2022-10-14
AnnouncementXML	Submission_2022-10-14_15:00:09.418.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	MarcTimmers
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-28 03:14:36	ID requested
⏵ 1	2022-10-14 15:00:10	announced
2	2023-11-14 07:50:34	announced	2023-11-14: Updated project metadata.

Dreijerink KMA, Ozyerli-Goknar E, Koidl S, van der Lelij EJ, van den Heuvel P, Kooijman JJ, Biniossek ML, Rodenburg KW, Nizamuddin S, Timmers HTM, Multi-omics analyses of MEN1 missense mutations identify disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity. Epigenetics Chromatin, 15(1):29(2022) [pubmed]

submitter keyword: greenCUT&RUN

H.Th. MarcTimmers
contact affiliation	DKFZ, Germany
contact email	m.timmers@dkfz-heidelberg.de
lab head
MarcTimmers
contact affiliation	German Cancer Consortium (DKTK), partner site Freiburg German Cancer Research Center (DKFZ) Foundation under Public Law c/o Department of Urology Zentrale Klinische Forschung (ZKF) Medical Center-University of Freiburg Breisacher Str. 66, 79106 Freiburg, Germany
contact email	m.timmers@dkfz-heidelberg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031928
     1. Label: PRIDE project
     2. Name: Multi-omics analysis of MEN1 missense mutations identifies disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity