7au2 | pdb_00007au2

Cryo-EM structure of human exostosin-like 3 (EXTL3)

Structural highlights

7au2 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	BMA, MAN, NAG
Activity:	Glucuronosyl-galactosyl-proteoglycan 4-alpha-N- acetylglucosaminyltransferase, with EC number 2.4.1.223
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). Important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs) (PubMed:28132690, PubMed:28148688). Required for the function of REG3A in regulating keratinocyte proliferation and differentiation (PubMed:22727489).^[1] ^[2] ^[3]

Publication Abstract from PubMed

Heparan sulfate is a highly modified O-linked glycan that performs diverse physiological roles in animal tissues. Though quickly modified, it is initially synthesised as a polysaccharide of alternating beta-D-glucuronosyl and N-acetyl-alpha-D-glucosaminyl residues by exostosins. These enzymes generally possess two glycosyltransferase domains (GT47 and GT64)-each thought to add one type of monosaccharide unit to the backbone. Although previous structures of murine exostosin-like 2 (EXTL2) provide insight into the GT64 domain, the rest of the bi-domain architecture is yet to be characterised; hence, how the two domains co-operate is unknown. Here, we report the structure of human exostosin-like 3 (EXTL3) in apo and UDP-bound forms. We explain the ineffectiveness of EXTL3's GT47 domain to transfer beta-D-glucuronosyl units, and we observe that, in general, the bi-domain architecture would preclude a processive mechanism of backbone extension. We therefore propose that heparan sulfate backbone polymerisation occurs by a simple dissociative mechanism.

The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis.,Wilson LFL, Dendooven T, Hardwick SW, Echevarria-Poza A, Tryfona T, Krogh KBRM, Chirgadze DY, Luisi BF, Logan DT, Mani K, Dupree P Nat Commun. 2022 Jun 8;13(1):3314. doi: 10.1038/s41467-022-31048-2. PMID:35676258^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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:https://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:https://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:https://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:https://dx.doi.org/10.1038/s41467-022-31048-2

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OCA

[1] 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:https://dx.doi.org/10.1016/j.immuni.2012.04.010

[2] 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:https://dx.doi.org/10.1016/j.ajhg.2017.01.013

[3] 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:https://dx.doi.org/10.1084/jem.20161525

[4] 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:https://dx.doi.org/10.1038/s41467-022-31048-2

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[2]

[3]

[4]

7au2 | pdb_00007au2

Cryo-EM structure of human exostosin-like 3 (EXTL3)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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