7ndl

From Proteopedia

Crystal structure of human GFAT-1 S205D

Structural highlights

7ndl 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 2.223Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GFPT1_HUMAN Defects in GFPT1 are the cause of myasthenia, congenital, with tubular aggregates, type 1 (CMSTA1) [MIM:610542. A congenital myasthenic syndrome characterized by onset of proximal muscle weakness in the first decade. Individuals with this condition have a recognizable pattern of weakness of shoulder and pelvic girdle muscles, and sparing of ocular or facial muscles. EMG classically shows a decremental response to repeated nerve stimulation, a sign of neuromuscular junction dysfunction. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors.^[1]

Function

GFPT1_HUMAN Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins.

Publication Abstract from PubMed

The hexosamine pathway (HP) is a key anabolic pathway whose product uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) is an essential precursor for glycosylation processes in mammals. It modulates the ER stress response and HP activation extends lifespan in Caenorhabditis elegans. The highly conserved glutamine fructose-6-phosphate amidotransferase 1 (GFAT-1) is the rate-limiting HP enzyme. GFAT-1 activity is modulated by UDP-GlcNAc feedback inhibition and via phosphorylation by protein kinase A (PKA). Molecular consequences of GFAT-1 phosphorylation, however, remain poorly understood. Here, we identify the GFAT-1 R203H substitution that elevates UDP-GlcNAc levels in C. elegans. In human GFAT-1, the R203H substitution interferes with UDP-GlcNAc inhibition and with PKA-mediated Ser205 phosphorylation. Our data indicate that phosphorylation affects the interactions of the two GFAT-1 domains to control catalytic activity. Notably, Ser205 phosphorylation has two discernible effects: it lowers baseline GFAT-1 activity and abolishes UDP-GlcNAc feedback inhibition. PKA controls the HP by uncoupling the metabolic feedback loop of GFAT-1.

Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1.,Ruegenberg S, Mayr FAMC, Atanassov I, Baumann U, Denzel MS Nat Commun. 2021 Apr 12;12(1):2176. doi: 10.1038/s41467-021-22320-y. PMID:33846315^[2]

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

References

↑ Senderek J, Muller JS, Dusl M, Strom TM, Guergueltcheva V, Diepolder I, Laval SH, Maxwell S, Cossins J, Krause S, Muelas N, Vilchez JJ, Colomer J, Mallebrera CJ, Nascimento A, Nafissi S, Kariminejad A, Nilipour Y, Bozorgmehr B, Najmabadi H, Rodolico C, Sieb JP, Steinlein OK, Schlotter B, Schoser B, Kirschner J, Herrmann R, Voit T, Oldfors A, Lindbergh C, Urtizberea A, von der Hagen M, Hubner A, Palace J, Bushby K, Straub V, Beeson D, Abicht A, Lochmuller H. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet. 2011 Feb 11;88(2):162-72. doi: 10.1016/j.ajhg.2011.01.008. PMID:21310273 doi:10.1016/j.ajhg.2011.01.008
↑ Ruegenberg S, Mayr FAMC, Atanassov I, Baumann U, Denzel MS. Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1. Nat Commun. 2021 Apr 12;12(1):2176. doi: 10.1038/s41467-021-22320-y. PMID:33846315 doi:http://dx.doi.org/10.1038/s41467-021-22320-y