PXD058951

PXD058951 is an original dataset announced via ProteomeXchange.

Title	Marfan syndrome variation of the POGLUT2 and POGLUT3 consensus sequence can produce aberrant fibrillin-1 O-glucosylation
Description	Fibrillin-1 (FBN1) is an essential component of the extracellular matrix, forming microfibril bundles that are important for proper development of elastic tissues found in the aorta and lung, as well as non-elastic tissue found in the eyes and skeleton. Many missense mutations in the FBN1 gene are associated with Marfan syndrome (MFS), a common developmental disorder. FBN1 contains 47 Epidermal Growth Factor-Like (EGF) repeats, which are protein domains characterized by six cysteines and three disulfide bonds. Over half of these EGF repeats are modified with an O-glucose monosaccharide added by Protein O-glucosyltransferase 2 and/or 3 (POGLUT2/3). Previous studies showed that O-glucose modifies the serine within the putative consensus sequence between cysteines 3 and 4: C3-x-N-T-x-G-S-F/Y-x-C4. These residues are common among modified EGFs, but it is unknown if they are required for O-glucosylation. To address this, we used a glycoproteomic approach by analyzing O-glucosylation levels of individual EGF repeats from overexpressed N-terminal FBN1 variants in HEK293T cells. Surprisingly, only the serine (S) was required for O-glucosylation, leading to the revised consensus sequence, C3-x-x-x-x-x-S-x-x-C4. Using this open consensus in database searches, the possible number of POGLUT2/3 substrates in humans has doubled. While some variants displayed reduced O-glucose monosaccharide modification, other variants, including MFS variants, displayed elongation of the O-glucose monosaccharide by additional glycosyltransferases. MFS variants reduction or elongation of O-glucose warrants further investigation on their influence on FBN1 function, which could play a role in the molecular mechanism of the disease.
HostingRepository	PanoramaPublic
AnnounceDate	2025-03-20
AnnouncementXML	Submission_2025-03-20_10:25:56.671.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Nicholas Kegley
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	Methyl; Hex(2)NeuAc(1); Hex(1)Pent(2); Oxidation; Hex(1)Pent(1); Glu->pyro-Glu; Hex(1)HexNAc(1)NeuAc(1); Pentose; Pent(2); Dimethyl; Hex(2); Carbamidomethyl; dHex; Hex; Gln->pyro-Glu; HexNAc; Hex(1)HexNAc(1); Pyro-carbamidomethyl; Deamidated; Trimethyl; Dioxidation
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-17 14:07:09	ID requested
⏵ 1	2025-03-20 10:25:57	announced

Kegley, N. R., Ito, A., Williamson, D. B., McArdle, C. C., and Haltiwanger, R. S. Marfan syndrome variation of the POGLUT2 and POGLUT3 consensus sequence can produce aberrant fibrillin-1 O-glucosylation. Journal of Biological Chemistry

submitter keyword: extracellular matrix, fibrillin, glycoprotein, glycosyltransferase, mass spectrometry, Marfan syndrome, O-glucose, POGLUT2, POGLUT3

Robert Haltiwanger
contact affiliation	Univesity of Georgia
contact email	rhalti@uga.edu
lab head
Nicholas Kegley
contact affiliation	University of Georgia
contact email	nkegley@uga.edu
dataset submitter

Panorama Public dataset URI