PXD018902 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | O-Fucosylation of ADAMTSL2 Thrombospondin Type 1 Repeats is Required for Secretion and is Impacted by Geleophysic Dysplasia-Causing Mutations |
Description | A disintegrin-like and metalloprotease domain with thrombospondin type 1 repeats-like 2 (ADAMTSL2) is a matricellular protein that interacts with latent TGF-b binding protein 1 and fibrillin-1. ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder named geleophysic dysplasia 1 (GPHYSD1, OMIM #231050), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for serine or threonine glycosylation by protein O-fucosyltransferase 2 (POFUT2). O-fucose modified TSRs are subsequently elongated to a Glucoseď˘1-3Fucose (GlcFuc) disaccharide by b3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS, OMIM #261540), which is characterized by skeletal defects similar to those of GPHYSD1. Several ADAMTSL2 TSRs have consensus sequences for C-mannosylation, and one TSR contains a sequon for N-glycosylation that overlaps with an O-fucosylation site. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O-fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used mass spectrometry to identify glycan modifications at the predicted consensus sequences. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O-fucosylation sites and variable mannose stoichiometry at C-mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2 knockout but not in B3GLCT knockout cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients lacking B3GLCT. In contrast, secretion of mouse ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6) was significantly reduced in HEK293T cells. Moreover, S641L eliminated O-fucosylation of TSR3. Combined these results provide strong evidence that developmental abnormalities in GPHYSD1 patients with this mutation are caused by loss of O-fucosylation on TSR3 and impaired ADAMTSL2 secretion. |
HostingRepository | PRIDE |
AnnounceDate | 2020-10-01 |
AnnouncementXML | Submission_2020-09-30_22:54:08.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Ao Zhang |
SpeciesList | scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; |
ModificationList | monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2020-04-29 08:10:47 | ID requested | |
⏵ 1 | 2020-09-30 22:54:08 | announced | |
Publication List
Zhang A, Berardinelli SJ, Leonhard-Melief C, Vasudevan D, Liu TW, Taibi A, Giannone S, Apte SS, Holdener BC, Haltiwanger RS, Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations. J Biol Chem, 295(46):15742-15753(2020) [pubmed] |
Keyword List
submitter keyword: Thrombospondin Type 1 Repeats, TSR glycosylation, ADAMTSL2 O-fucosylation, Geleophysic Dysplasia |
Contact List
Robert S. Haltiwanger |
contact affiliation | Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, The University of Georgia, U.S.A. |
contact email | rhalti@uga.edu |
lab head | |
Ao Zhang |
contact affiliation | The University of Georgia |
contact email | az59150@uga.edu |
dataset submitter | |
Full Dataset Link List
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/2020/10/PXD018902 |
PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD018902
- Label: PRIDE project
- Name: O-Fucosylation of ADAMTSL2 Thrombospondin Type 1 Repeats is Required for Secretion and is Impacted by Geleophysic Dysplasia-Causing Mutations