7au2
From Proteopedia
Cryo-EM structure of human exostosin-like 3 (EXTL3)
Structural highlights
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 PubMedHeparan 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
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Categories: Glucuronosyl-galactosyl-proteoglycan 4-alpha-N- acetylglucosaminyltransferase | Large Structures | Chirgadze, D Y | Dendooven, T | Dupree, P | Hardwick, S W | Logan, D T | Luisi, B F | Mani, K | Wilson, L F.L | Glycosyltransferase | Heparan | N-acetylglucosaminyltransferase | Transferase
