Universität zu Köln

Ruegenberg, Sabine, Horn, Moritz ORCID: 0000-0002-5324-7256, Pichlo, Christian ORCID: 0000-0002-3156-5667, Allmeroth, Kira, Baumann, Ulrich and Denzel, Martin S. (2020). Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

Glutamine fructose-6-phosphate amidotransferase (GFAT) is the key enzyme in the hexosamine pathway (HP) that produces uridine 5-diphospho-N-acetyl-d-glucosamine (UDP-GlcNAc), linking energy metabolism with posttranslational protein glycosylation. In Caenorhabditis elegans, we previously identified gfat-1 gain-of-function mutations that elevate UDP-GlcNAc levels, improve protein homeostasis, and extend lifespan. GFAT is highly conserved, but the gain-of-function mechanism and its relevance in mammalian cells remained unclear. Here, we present the full-length crystal structure of human GFAT-1 in complex with various ligands and with important mutations. UDP-GlcNAc directly interacts with GFAT-1, inhibiting catalytic activity. The longevity-associated G451E variant shows drastically reduced sensitivity to UDP-GlcNAc inhibition in enzyme activity assays. Our structural and functional data point to a critical role of the interdomain linker in UDP-GlcNAc inhibition. In mammalian cells, the G451E variant potently activates the HP. Therefore, GFAT-1 gain-of-function through loss of feedback inhibition constitutes a potential target for the treatment of age-related proteinopathies. p id=Par Mutations in the hexosamine pathway key enzyme glutamine fructose-6-phosphate amidotransferase (GFAT-1) improve protein quality control and extend C. elegans lifespan. Here the authors present the crystal structures of full-length human GFAT-1 alone and with bound ligands and perform activity assays, which show that gain-of-function in the longevity-associated G451E variant is caused by a loss of feedback regulation.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ruegenberg, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Horn, Moritz UNSPECIFIED orcid.org/0000-0002-5324-7256 UNSPECIFIED Pichlo, Christian UNSPECIFIED orcid.org/0000-0002-3156-5667 UNSPECIFIED Allmeroth, Kira UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Denzel, Martin S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-345452
DOI:	10.1038/s41467-020-14524-5
Journal or Publication Title:	Nat. Commun.
Volume:	11
Number:	1
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN GLUTAMINE-FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE; FRUCTOSE 6-PHOSPHATE AMIDOTRANSFERASE; ANGSTROM CRYSTAL-STRUCTURE; GLUCOSAMINE-6-PHOSPHATE SYNTHASE; O-GLCNACYLATION; L-GLUTAMINE; PHOSPHORYLATION; IDENTIFICATION; PURIFICATION; DOMAINS Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/34545