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O- Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations.
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- Additional Information
- Source:
Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
- Publication Information:
Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
- Subject Terms:
- Abstract:
ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder, geleophysic dysplasia 1 (GPHYSD1), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 is a matricellular protein previously shown to interact with latent transforming growth factor-β binding protein 1 and influence assembly of fibrillin 1 microfibrils. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for O -fucosylation by protein O- fucosyltransferase 2 (POFUT2). O- fucose-modified TSRs are subsequently elongated to a glucose β1-3-fucose (GlcFuc) disaccharide by β1,3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS), which is characterized by skeletal defects similar to GPHYSD1. Several ADAMTSL2 TSRs also have consensus sequences for C- mannosylation. 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 MS to identify glycan modifications at predicted consensus sequences on mouse ADAMTSL2. 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 -/- but not in B3GLCT -/- cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients. In contrast, secretion was significantly reduced for ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6), and S641L eliminated O- fucosylation of TSR3. These results provide evidence that abnormalities in GPHYSD1 patients with this mutation are caused by loss of O- fucosylation on TSR3 and impaired ADAMTSL2 secretion.
Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.
(© 2020 Zhang et al.)
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- Grant Information:
R01 CA123071 United States CA NCI NIH HHS; R01 HD090156 United States HD NICHD NIH HHS; R01 HD096030 United States HD NICHD NIH HHS
- Contributed Indexing:
Keywords: ADAMTSL2; C-mannosylation; O-fucosylation; TSR; cell biology; extracellular matrix; geleophysic dysplasia; glycoprotein secretion; glycosylation; mass spectrometry
- Accession Number:
0 (Adamtsl2 protein, mouse)
0 (Disaccharides)
0 (Extracellular Matrix Proteins)
0 (Recombinant Proteins)
EC 2.4.- (B3glct protein, mouse)
EC 2.4.- (Glycosyltransferases)
EC 2.4.1.- (Fucosyltransferases)
EC 2.4.1.221 (PoFut2 protein, mouse)
EC 3.4.24.- (ADAMTS Proteins)
PHA4727WTP (Mannose)
- Subject Terms:
Acromicric dysplasia
- Publication Date:
Date Created: 20200911 Date Completed: 20210309 Latest Revision: 20211114
- Publication Date:
20231215
- Accession Number:
PMC7667967
- Accession Number:
10.1074/jbc.RA120.014557
- Accession Number:
32913123
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