8w4j | pdb_00008w4j

Cryo-EM structure of the KLHL22 E3 ligase bound to human glutamate dehydrogenase I

Structural highlights

8w4j is a 8 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:	Electron Microscopy, Resolution 3.06Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DHE3_HUMAN Defects in GLUD1 are the cause of familial hyperinsulinemic hypoglycemia type 6 (HHF6) [MIM:606762; also known as hyperinsulinism-hyperammonemia syndrome (HHS). Familial hyperinsulinemic hypoglycemia [MIM:256450, also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. In HHF6 elevated oxidation rate of glutamate to alpha-ketoglutarate stimulates insulin secretion in the pancreatic beta cells, while they impair detoxification of ammonium in the liver.^[1] ^[2] ^[3] ^[4]

Function

DHE3_HUMAN May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate (By similarity).

Publication Abstract from PubMed

CULLIN-RING ligases constitute the largest group of E3 ubiquitin ligases. While some CULLIN family members recruit adapters before engaging further with different substrate receptors, homo-dimeric BTB-Kelch family proteins combine adapter and substrate receptor into a single polypeptide for the CULLIN3 family. However, the entire structural assembly and molecular details have not been elucidated to date. Here, we present a cryo-EM structure of the CULLIN3(RBX1) in complex with Kelch-like protein 22 (KLHL22) and a mitochondrial glutamate dehydrogenase complex I (GDH1) at 3.06 A resolution. The structure adopts a W-shaped architecture formed by E3 ligase dimers. Three CULLIN3(KLHL22-RBX1) dimers were found to be dynamically associated with a single GDH1 hexamer. CULLIN3(KLHL22-RBX1) ligase mediated the polyubiquitination of GDH1 in vitro. Together, these results enabled the establishment of a structural model for understanding the complete assembly of BTB-Kelch proteins with CULLIN3 and how together they recognize oligomeric substrates and target them for ubiquitination.

Cryo-EM structure of the KLHL22 E3 ligase bound to an oligomeric metabolic enzyme.,Teng F, Wang Y, Liu M, Tian S, Stjepanovic G, Su MY Structure. 2023 Sep 22:S0969-2126(23)00325-8. doi: 10.1016/j.str.2023.09.002. PMID:37788672^[5]

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

References

↑ Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998 May 7;338(19):1352-7. PMID:9571255
↑ Miki Y, Taki T, Ohura T, Kato H, Yanagisawa M, Hayashi Y. Novel missense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism-hyperammonemia syndrome. J Pediatr. 2000 Jan;136(1):69-72. PMID:10636977
↑ Santer R, Kinner M, Passarge M, Superti-Furga A, Mayatepek E, Meissner T, Schneppenheim R, Schaub J. Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome. Hum Genet. 2001 Jan;108(1):66-71. PMID:11214910
↑ MacMullen C, Fang J, Hsu BY, Kelly A, de Lonlay-Debeney P, Saudubray JM, Ganguly A, Smith TJ, Stanley CA. Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab. 2001 Apr;86(4):1782-7. PMID:11297618
↑ Teng F, Wang Y, Liu M, Tian S, Stjepanovic G, Su MY. Cryo-EM structure of the KLHL22 E3 ligase bound to an oligomeric metabolic enzyme. Structure. 2023 Sep 22:S0969-2126(23)00325-8. PMID:37788672 doi:10.1016/j.str.2023.09.002

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OCA

[1] Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998 May 7;338(19):1352-7. PMID:9571255

[2] Miki Y, Taki T, Ohura T, Kato H, Yanagisawa M, Hayashi Y. Novel missense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism-hyperammonemia syndrome. J Pediatr. 2000 Jan;136(1):69-72. PMID:10636977

[3] Santer R, Kinner M, Passarge M, Superti-Furga A, Mayatepek E, Meissner T, Schneppenheim R, Schaub J. Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome. Hum Genet. 2001 Jan;108(1):66-71. PMID:11214910

[4] MacMullen C, Fang J, Hsu BY, Kelly A, de Lonlay-Debeney P, Saudubray JM, Ganguly A, Smith TJ, Stanley CA. Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab. 2001 Apr;86(4):1782-7. PMID:11297618

[5] Teng F, Wang Y, Liu M, Tian S, Stjepanovic G, Su MY. Cryo-EM structure of the KLHL22 E3 ligase bound to an oligomeric metabolic enzyme. Structure. 2023 Sep 22:S0969-2126(23)00325-8. PMID:37788672 doi:10.1016/j.str.2023.09.002

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8w4j | pdb_00008w4j

Cryo-EM structure of the KLHL22 E3 ligase bound to human glutamate dehydrogenase I

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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