8imy

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Cryo-EM structure of GPI-T (inactive mutant) with GPI and proULBP2, a proprotein substrate

Structural highlights

8imy is a 6 chain structure with sequence from Clavularia sp. and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.22Å
Ligands:	, , , , , , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GPAA1_HUMAN Neurodevelopmental delay-seizures-ophthalmic anomalies-osteopenia-cerebellar atrophy syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

GPAA1_HUMAN Component of the GPI transamidase complex, necessary for transfer of GPI to proteins (PubMed:34576938). Essential for GPI-anchoring of precursor proteins but not for GPI synthesis. Acts before or during formation of the carbonyl intermediate.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Many eukaryotic receptors and enzymes rely on glycosylphosphatidylinositol (GPI) anchors for membrane localization and function. The transmembrane complex GPI-T recognizes diverse proproteins at a signal peptide region that lacks consensus sequence and replaces it with GPI via a transamidation reaction. How GPI-T maintains broad specificity while preventing unintentional cleavage is unclear. Here, substrates- and products-bound human GPI-T structures identify subsite features that enable broad proprotein specificity, inform catalytic mechanism, and reveal a multilevel safeguard mechanism against its promiscuity. In the absence of proproteins, the catalytic site is invaded by a locally stabilized loop. Activation requires energetically unfavorable rearrangements that transform the autoinhibitory loop into crucial catalytic cleft elements. Enzyme-proprotein binding in the transmembrane and luminal domains respectively powers the conformational rearrangement and induces a competent cleft. GPI-T thus integrates various weak specificity regions to form strong selectivity and prevent accidental activation. These findings provide important mechanistic insights into GPI-anchored protein biogenesis.

Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis.,Xu Y, Li T, Zhou Z, Hong J, Chao Y, Zhu Z, Zhang Y, Qu Q, Li D Nat Commun. 2023 Sep 8;14(1):5520. doi: 10.1038/s41467-023-41281-y. PMID:37684232^[4]

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

References

↑ Nguyen TTM, Murakami Y, Sheridan E, Ehresmann S, Rousseau J, St-Denis A, Chai G, Ajeawung NF, Fairbrother L, Reimschisel T, Bateman A, Berry-Kravis E, Xia F, Tardif J, Parry DA, Logan CV, Diggle C, Bennett CP, Hattingh L, Rosenfeld JA, Perry MS, Parker MJ, Le Deist F, Zaki MS, Ignatius E, Isohanni P, Lönnqvist T, Carroll CJ, Johnson CA, Gleeson JG, Kinoshita T, Campeau PM. Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia. Am J Hum Genet. 2017 Nov 2;101(5):856-865. PMID:29100095 doi:10.1016/j.ajhg.2017.09.020
↑ Liu SS, Jin F, Liu YS, Murakami Y, Sugita Y, Kato T, Gao XD, Kinoshita T, Hattori M, Fujita M. Functional Analysis of the GPI Transamidase Complex by Screening for Amino Acid Mutations in Each Subunit. Molecules. 2021 Sep 8;26(18):5462. PMID:34576938 doi:10.3390/molecules26185462
↑ Hiroi Y, Komuro I, Chen R, Hosoda T, Mizuno T, Kudoh S, Georgescu SP, Medof ME, Yazaki Y. Molecular cloning of human homolog of yeast GAA1 which is required for attachment of glycosylphosphatidylinositols to proteins. FEBS Lett. 1998 Jan 16;421(3):252-8. PMID:9468317 doi:10.1016/s0014-5793(97)01576-7
↑ Xu Y, Li T, Zhou Z, Hong J, Chao Y, Zhu Z, Zhang Y, Qu Q, Li D. Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis. Nat Commun. 2023 Sep 8;14(1):5520. PMID:37684232 doi:10.1038/s41467-023-41281-y