8c6i
From Proteopedia
TMEM2 ectodomain
Structural highlights
FunctionCEIP2_HUMAN Cell surface hyaluronidase that mediates the initial cleavage of extracellular high-molecular-weight hyaluronan into intermediate-size hyaluronan of approximately 10-5 kDa fragments (PubMed:37527776). Very specific to hyaluronan; not able to cleave chondroitin sulfate or dermatan sulfate. Has an essential function in systemic hyaluronan catabolism and turnover and regulates cell adhesion and migration via hyaluronan degradation at focal adhesion sites (By similarity). Acts as a regulator of angiogenesis and heart morphogenesis by mediating degradation of extracellular hyaluronan, thereby regulating VEGF signaling (By similarity).[UniProtKB:A3KPQ7][UniProtKB:Q5FWI3][1] Publication Abstract from PubMedBackground: Hyaluronic acid (HA) is a major polysaccharide component of the extracellular matrix. HA has essential functions in tissue architecture and the regulation of cell behaviour. HA turnover needs to be finely balanced. Increased HA degradation is associated with cancer, inflammation, and other pathological situations. Transmembrane protein 2 (TMEM2) is a cell surface protein that has been reported to degrade HA into ~5 kDa fragments and play an essential role in systemic HA turnover. Methods: We produced the soluble TMEM2 ectodomain (residues 106-1383; sTMEM2) in human embryonic kidney cells (HEK293) and determined its structure using X-ray crystallography. We tested sTMEM2 hyaluronidase activity using fluorescently labelled HA and size fractionation of reaction products. We tested HA binding in solution and using a glycan microarray. Results: Our crystal structure of sTMEM2 confirms a remarkably accurate prediction by AlphaFold. sTMEM2 contains a parallel beta-helix typical of other polysaccharide-degrading enzymes, but an active site cannot be assigned with confidence. A lectin-like domain is inserted into the beta-helix and predicted to be functional in carbohydrate binding. A second lectin-like domain at the C-terminus is unlikely to bind carbohydrates. We did not observe HA binding in two assay formats, suggesting a modest affinity at best. Unexpectedly, we were unable to observe any HA degradation by sTMEM2. Our negative results set an upper limit for k (cat) of approximately 10 (-5) min (-1). Conclusions: Although sTMEM2 contains domain types consistent with its suggested role in TMEM2 degradation, its hyaluronidase activity was undetectable. HA degradation by TMEM2 may require additional proteins and/or localisation at the cell surface. Structure of the transmembrane protein 2 (TMEM2) ectodomain and its apparent lack of hyaluronidase activity.,Niu M, McGrath M, Sammon D, Gardner S, Morgan RM, Di Maio A, Liu Y, Bubeck D, Hohenester E Wellcome Open Res. 2023 May 2;8:76. doi: 10.12688/wellcomeopenres.18937.2. , eCollection 2023. PMID:37234743[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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