Effects of the T337M and G391V Disease-related Variants on Human Phosphoglucomutase 1: Structural Disruptions Large and Small

Overview

Journal Acta Crystallogr F Struct Biol Commun

Specialty Chemistry

Date 2022 May 4

PMID 35506765

Authors

Kyle M Stiers

Luckio F Owuocha

Lesa J Beamer

Affiliations

Soon will be listed here.

Abstract

Phosphoglucomutase 1 (PGM1) plays a central role in glucose homeostasis in human cells. Missense variants of this enzyme cause an inborn error of metabolism, which is categorized as a congenital disorder of glycosylation. Here, two disease-related variants of PGM1, T337M and G391V, which are both located in domain 3 of the four-domain protein, were characterized via X-ray crystallography and biochemical assays. The studies show multiple impacts resulting from these dysfunctional variants, including both short- and long-range structural perturbations. In the T337M variant these are limited to a small shift in an active-site loop, consistent with reduced enzyme activity. In contrast, the G391V variant produces a cascade of structural perturbations, including displacement of both the catalytic phosphoserine and metal-binding loops. This work reinforces several themes that were found in prior studies of dysfunctional PGM1 variants, including increased structural flexibility and the outsized impacts of mutations affecting interdomain interfaces. The molecular mechanisms of PGM1 variants have implications for newly described inherited disorders of related enzymes.

References

Stiers K, Beamer L . Assessment and Impacts of Phosphorylation on Protein Flexibility of the α-d-Phosphohexomutases. Methods Enzymol. 2018; 607:241-267. DOI: 10.1016/bs.mie.2018.04.003. View

Nolting K, Park J, Tegtmeyer L, Zuhlsdorf A, Gruneberg M, Rust S . Limitations of galactose therapy in phosphoglucomutase 1 deficiency. Mol Genet Metab Rep. 2017; 13:33-40. PMC: 5540825. DOI: 10.1016/j.ymgmr.2017.07.010. View

Liu X, Bian W, Wang J, Ye T, Li B, Liu D . Heterozygous Variants Are Associated With Idiopathic Focal Epilepsy With Incomplete Penetrance. Front Genet. 2020; 11:559080. PMC: 7597759. DOI: 10.3389/fgene.2020.559080. View

Perez B, Medrano C, Ecay M, Ruiz-Sala P, Martinez-Pardo M, Ugarte M . A novel congenital disorder of glycosylation type without central nervous system involvement caused by mutations in the phosphoglucomutase 1 gene. J Inherit Metab Dis. 2012; 36(3):535-42. DOI: 10.1007/s10545-012-9525-7. View

Morava E, Wong S, Lefeber D . Disease severity and clinical outcome in phosphosglucomutase deficiency. J Inherit Metab Dis. 2014; 38(2):207-9. PMC: 4344407. DOI: 10.1007/s10545-014-9769-5. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Radenkovic S, Bird M, Emmerzaal T, Wong S, Felgueira C, Stiers K . The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG. Am J Hum Genet. 2019; 104(5):835-846. PMC: 6506806. DOI: 10.1016/j.ajhg.2019.03.003. View

Evans P, Murshudov G . How good are my data and what is the resolution?. Acta Crystallogr D Biol Crystallogr. 2013; 69(Pt 7):1204-14. PMC: 3689523. DOI: 10.1107/S0907444913000061. View

Ding Y, Li N, Chang G, Li J, Yao R, Shen Y . Clinical and molecular genetic characterization of two patients with mutations in the phosphoglucomutase 1 (PGM1) gene. J Pediatr Endocrinol Metab. 2018; 31(7):781-788. DOI: 10.1515/jpem-2017-0551. View

10.

Beamer L . Enzyme dysfunction at atomic resolution: Disease-associated variants of human phosphoglucomutase-1. Biochimie. 2020; 183:44-48. DOI: 10.1016/j.biochi.2020.08.017. View

11.

Fraser J, van den Bedem H, Samelson A, Lang P, Holton J, Echols N . Accessing protein conformational ensembles using room-temperature X-ray crystallography. Proc Natl Acad Sci U S A. 2011; 108(39):16247-52. PMC: 3182744. DOI: 10.1073/pnas.1111325108. View

12.

Sassi A, Lazaroski S, Wu G, Haslam S, Fliegauf M, Mellouli F . Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J Allergy Clin Immunol. 2014; 133(5):1410-9, 1419.e1-13. PMC: 4825677. DOI: 10.1016/j.jaci.2014.02.025. View

13.

Schjoldager K, Narimatsu Y, Joshi H, Clausen H . Global view of human protein glycosylation pathways and functions. Nat Rev Mol Cell Biol. 2020; 21(12):729-749. DOI: 10.1038/s41580-020-00294-x. View

14.

Ondruskova N, Honzik T, Vondrackova A, Tesarova M, Zeman J, Hansikova H . Glycogen storage disease-like phenotype with central nervous system involvement in a PGM1-CDG patient. Neuro Endocrinol Lett. 2014; 35(2):137-41. View

15.

Hackney D, McGoff M . Nucleotide-free kinesin motor domains reversibly convert to an inactive conformation with characteristics of a molten globule. Arch Biochem Biophys. 2016; 608:42-51. PMC: 5159748. DOI: 10.1016/j.abb.2016.08.019. View

16.

Karplus P, Diederichs K . Linking crystallographic model and data quality. Science. 2012; 336(6084):1030-3. PMC: 3457925. DOI: 10.1126/science.1218231. View

17.

Stojkovic T, Vissing J, Petit F, Piraud M, Orngreen M, Andersen G . Muscle glycogenosis due to phosphoglucomutase 1 deficiency. N Engl J Med. 2009; 361(4):425-7. DOI: 10.1056/NEJMc0901158. View

18.

Muenks A, Stiers K, Beamer L . Sequence-structure relationships, expression profiles, and disease-associated mutations in the paralogs of phosphoglucomutase 1. PLoS One. 2017; 12(8):e0183563. PMC: 5570346. DOI: 10.1371/journal.pone.0183563. View

19.

Yan-Wai Wong S, Beamer L, Gadomski T, Honzik T, Mohamed M, Wortmann S . Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency. J Pediatr. 2016; 175:130-136.e8. DOI: 10.1016/j.jpeds.2016.04.021. View

20.

Timal S, Hoischen A, Lehle L, Adamowicz M, Huijben K, Sykut-Cegielska J . Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. Hum Mol Genet. 2012; 21(19):4151-61. DOI: 10.1093/hmg/dds123. View