| Structural highlights
8og4 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.1Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
EXTL3_HUMAN Skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome. The disease is caused by variants affecting the gene represented in this entry.
Function
EXTL3_HUMAN Glycosyltransferase which regulates the biosynthesis of heparan sulfate (HS) (PubMed:28132690, PubMed:28148688). Initiates HS synthesis by transferring the first N-acetyl-alpha-D-glucosamine (alpha-GlcNAc) residue (GlcNAcT-I activity) to the tetrasaccharide linker (GlcA-Gal-Gal-Xyl-)Ser core linker (PubMed:11390981, PubMed:35676258). May also transfer alpha-GlcNAc residues during HS elongation (GlcNAcT-II activity) (PubMed:11390981, PubMed:35676258). Lacks glucuronyl transferase II (GlcAT-II) activity (PubMed:11390981, PubMed:35676258). Important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs) (PubMed:11390981, PubMed:22727489, PubMed:28132690, PubMed:28148688, PubMed:35676258). Through the synthesis of HS, regulates postnatal pancreatic islet maturation and insulin secretion (By similarity).[UniProtKB:Q9WVL6][1] [2] [3] [4] [5] Receptor for REG3A, REG3B and REG3G, induces the activation of downstream signaling pathways such as PI3K-AKT or RAS-RAF-MEK-ERK signaling pathway (PubMed:22727489, PubMed:27830702, PubMed:34099862). Required for the function of REG3A in regulating keratinocyte proliferation and differentiation (PubMed:22727489). Required for the inhibition of skin inflammation mediated by REG3A through the activation of PI3K-AKT-STAT3 pathway (PubMed:27830702). Required for the function of REG3A and REG3G in glucose tolerance in pancreas (PubMed:19158046). Expressed in microglia, is activated by nociceptor-derived REG3G in response to endotoxins, leading to the inhibition of kynurenine pathway to prevent endotoxic death (By similarity).[UniProtKB:Q9WVL6][6] [7] [8] [9]
Publication Abstract from PubMed
Two major glycosaminoglycan types, heparan sulfate (HS) and chondroitin sulfate (CS), control many aspects of development and physiology in a type-specific manner. HS and CS are attached to core proteins via a common linker tetrasaccharide, but differ in their polymer backbones. How core proteins are specifically modified with HS or CS has been an enduring mystery. By reconstituting glycosaminoglycan biosynthesis in vitro, we establish that the CS-initiating N-acetylgalactosaminyltransferase CSGALNACT2 modifies all glycopeptide substrates equally, whereas the HS-initiating N-acetylglucosaminyltransferase EXTL3 is selective. Structure-function analysis reveals that acidic residues in the glycopeptide substrate and a basic exosite in EXTL3 are critical for specifying HS biosynthesis. Linker phosphorylation by the xylose kinase FAM20B accelerates linker synthesis and initiation of both HS and CS, but has no effect on the subsequent polymerisation of the backbone. Our results demonstrate that modification with CS occurs by default and must be overridden by EXTL3 to produce HS.
Molecular mechanism of decision-making in glycosaminoglycan biosynthesis.,Sammon D, Krueger A, Busse-Wicher M, Morgan RM, Haslam SM, Schumann B, Briggs DC, Hohenester E Nat Commun. 2023 Oct 13;14(1):6425. doi: 10.1038/s41467-023-42236-z. PMID:37828045[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kim BT, Kitagawa H, Tamura J, Saito T, Kusche-Gullberg M, Lindahl U, Sugahara K. Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode alpha 1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7176-81. PMID:11390981 doi:10.1073/pnas.131188498
- ↑ Lai Y, Li D, Li C, Muehleisen B, Radek KA, Park HJ, Jiang Z, Li Z, Lei H, Quan Y, Zhang T, Wu Y, Kotol P, Morizane S, Hata TR, Iwatsuki K, Tang C, Gallo RL. The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury. Immunity. 2012 Jul 27;37(1):74-84. doi: 10.1016/j.immuni.2012.04.010. Epub 2012, Jun 21. PMID:22727489 doi:http://dx.doi.org/10.1016/j.immuni.2012.04.010
- ↑ Oud MM, Tuijnenburg P, Hempel M, van Vlies N, Ren Z, Ferdinandusse S, Jansen MH, Santer R, Johannsen J, Bacchelli C, Alders M, Li R, Davies R, Dupuis L, Cale CM, Wanders RJA, Pals ST, Ocaka L, James C, Muller I, Lehmberg K, Strom T, Engels H, Williams HJ, Beales P, Roepman R, Dias P, Brunner HG, Cobben JM, Hall C, Hartley T, Le Quesne Stabej P, Mendoza-Londono R, Davies EG, de Sousa SB, Lessel D, Arts HH, Kuijpers TW. Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome. Am J Hum Genet. 2017 Feb 2;100(2):281-296. doi: 10.1016/j.ajhg.2017.01.013. Epub , 2017 Jan 26. PMID:28132690 doi:http://dx.doi.org/10.1016/j.ajhg.2017.01.013
- ↑ Volpi S, Yamazaki Y, Brauer PM, van Rooijen E, Hayashida A, Slavotinek A, Sun Kuehn H, Di Rocco M, Rivolta C, Bortolomai I, Du L, Felgentreff K, Ott de Bruin L, Hayashida K, Freedman G, Marcovecchio GE, Capuder K, Rath P, Luche N, Hagedorn EJ, Buoncompagni A, Royer-Bertrand B, Giliani S, Poliani PL, Imberti L, Dobbs K, Poulain FE, Martini A, Manis J, Linhardt RJ, Bosticardo M, Rosenzweig SD, Lee H, Puck JM, Zuniga-Pflucker JC, Zon L, Park PW, Superti-Furga A, Notarangelo LD. EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay. J Exp Med. 2017 Mar 6;214(3):623-637. doi: 10.1084/jem.20161525. Epub 2017 Feb 1. PMID:28148688 doi:http://dx.doi.org/10.1084/jem.20161525
- ↑ Wilson LFL, Dendooven T, Hardwick SW, Echevarria-Poza A, Tryfona T, Krogh KBRM, Chirgadze DY, Luisi BF, Logan DT, Mani K, Dupree P. The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis. Nat Commun. 2022 Jun 8;13(1):3314. doi: 10.1038/s41467-022-31048-2. PMID:35676258 doi:http://dx.doi.org/10.1038/s41467-022-31048-2
- ↑ Levetan CS, Upham LV, Deng S, Laury-Kleintop L, Kery V, Nolan R, Quinlan J, Torres C, El-Hajj RJ. Discovery of a human peptide sequence signaling islet neogenesis. Endocr Pract. 2008 Dec;14(9):1075-83. PMID:19158046 doi:10.4158/EP.14.9.1075
- ↑ Lai Y, Li D, Li C, Muehleisen B, Radek KA, Park HJ, Jiang Z, Li Z, Lei H, Quan Y, Zhang T, Wu Y, Kotol P, Morizane S, Hata TR, Iwatsuki K, Tang C, Gallo RL. The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury. Immunity. 2012 Jul 27;37(1):74-84. doi: 10.1016/j.immuni.2012.04.010. Epub 2012, Jun 21. PMID:22727489 doi:http://dx.doi.org/10.1016/j.immuni.2012.04.010
- ↑ Wu Y, Quan Y, Liu Y, Liu K, Li H, Jiang Z, Zhang T, Lei H, Radek KA, Li D, Wang Z, Lu J, Wang W, Ji S, Xia Z, Lai Y. Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes. Nat Commun. 2016 Nov 10;7:13393. PMID:27830702 doi:10.1038/ncomms13393
- ↑ Zhang H, Corredor ALG, Messina-Pacheco J, Li Q, Zogopoulos G, Kaddour N, Wang Y, Shi BY, Gregorieff A, Liu JL, Gao ZH. REG3A/REG3B promotes acinar to ductal metaplasia through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. Commun Biol. 2021 Jun 7;4(1):688. PMID:34099862 doi:10.1038/s42003-021-02193-z
- ↑ Sammon D, Krueger A, Busse-Wicher M, Morgan RM, Haslam SM, Schumann B, Briggs DC, Hohenester E. Molecular mechanism of decision-making in glycosaminoglycan biosynthesis. Nat Commun. 2023 Oct 13;14(1):6425. PMID:37828045 doi:10.1038/s41467-023-42236-z
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