Crystal structures of fukutin-related protein (FKRP), a ribitol-phosphate transferase related to muscular dystrophy.
Catalytic Domain
Crystallography, X-Ray
Glycopeptides
HEK293 Cells
Humans
Models, Molecular
Muscular Dystrophies
/ genetics
Nucleoside Diphosphate Sugars
/ chemistry
Pentosyltransferases
/ chemistry
Phosphates
/ metabolism
Polysaccharides
/ metabolism
Protein Conformation
Protein Domains
Ribitol
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 01 2020
16 01 2020
Historique:
received:
11
06
2019
accepted:
10
12
2019
entrez:
18
1
2020
pubmed:
18
1
2020
medline:
9
4
2020
Statut:
epublish
Résumé
α-Dystroglycan (α-DG) is a highly-glycosylated surface membrane protein. Defects in the O-mannosyl glycan of α-DG cause dystroglycanopathy, a group of congenital muscular dystrophies. The core M3 O-mannosyl glycan contains tandem ribitol-phosphate (RboP), a characteristic feature first found in mammals. Fukutin and fukutin-related protein (FKRP), whose mutated genes underlie dystroglycanopathy, sequentially transfer RboP from cytidine diphosphate-ribitol (CDP-Rbo) to form a tandem RboP unit in the core M3 glycan. Here, we report a series of crystal structures of FKRP with and without donor (CDP-Rbo) and/or acceptor [RboP-(phospho-)core M3 peptide] substrates. FKRP has N-terminal stem and C-terminal catalytic domains, and forms a tetramer both in crystal and in solution. In the acceptor complex, the phosphate group of RboP is recognized by the catalytic domain of one subunit, and a phosphate group on O-mannose is recognized by the stem domain of another subunit. Structure-based functional studies confirmed that the dimeric structure is essential for FKRP enzymatic activity.
Identifiants
pubmed: 31949166
doi: 10.1038/s41467-019-14220-z
pii: 10.1038/s41467-019-14220-z
pmc: PMC6965139
doi:
Substances chimiques
Glycopeptides
0
Nucleoside Diphosphate Sugars
0
Phosphates
0
Polysaccharides
0
cytidine diphosphate ribitol
3506-17-0
Ribitol
488-81-3
FKRP protein, human
EC 2.4.2.-
Pentosyltransferases
EC 2.4.2.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
303Références
Manya, H. & Endo, T. Glycosylation with ribitol-phosphate in mammals: New insights into the O-mannosyl glycan. BBA - Gen. Subj. 1861, 1–41 (2017).
doi: 10.1016/j.bbagen.2017.06.024
Yoshida-Moriguchi, T. & Campbell, K. P. Matriglycan: a novel polysaccharide that links dystroglycan to the basement membrane. Glycobiology 25, 702–713 (2015).
pubmed: 25882296
pmcid: 4453867
doi: 10.1093/glycob/cwv021
Endo, T. Glycobiology of α-dystroglycan and muscular dystrophy. J. Biochem. 157, 1–12 (2015).
pubmed: 25381372
doi: 10.1093/jb/mvu066
pmcid: 25381372
Michele, D. E. & Campbell, K. P. Dystrophin-glycoprotein complex: post-translational processing and dystroglycan function. J. Biol. Chem. 278, 15457–15460 (2003).
pubmed: 12556455
doi: 10.1074/jbc.R200031200
pmcid: 12556455
Yoshida-Moriguchi, T. et al. SGK196 is a glycosylation-specific O-mannose kinase required for dystroglycan function. Science 341, 896–899 (2013).
pubmed: 23929950
doi: 10.1126/science.1239951
pmcid: 23929950
Manya, H. et al. Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proc. Natl Acad. Sci. USA 101, 500–505 (2004).
pubmed: 14699049
doi: 10.1073/pnas.0307228101
pmcid: 14699049
Yoshida, A. et al. Muscular dystrophy and neuronal migration disorder caused by mutations in α glycosyltransferase, POMGnT1. Dev. Cell 1, 717–724 (2001).
pubmed: 11709191
doi: 10.1016/S1534-5807(01)00070-3
pmcid: 11709191
Kaneko, M. et al. A novel beta(1,6)-N-acetylglucosaminyltransferase V (GnT-VB). FEBS Lett. 554, 515–519 (2003).
pubmed: 14623122
doi: 10.1016/S0014-5793(03)01234-1
pmcid: 14623122
Inamori, K. et al. Molecular cloning and characterization of human GnT-IX, a novel beta1,6-N-acetylglucosaminyltransferase that is specifically expressed in the brain. J. Biol. Chem. 278, 43102–43109 (2003).
pubmed: 12941944
doi: 10.1074/jbc.M308255200
pmcid: 12941944
Manya, H. et al. The muscular dystrophy gene TMEM5 encodes a ribitol β1,4-xylosyltransferase required for the functional glycosylation of dystroglycan. J. Biol. Chem. 291, 24618–24627 (2016).
pubmed: 27733679
pmcid: 5114413
doi: 10.1074/jbc.M116.751917
Kanagawa, M. et al. Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy. Cell Rep. 14, 2209–2223 (2016).
pubmed: 26923585
doi: 10.1016/j.celrep.2016.02.017
pmcid: 26923585
Willer, T. et al. The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation. eLife 3, 303 (2014).
doi: 10.7554/eLife.03941
Praissman, J. L. et al. B4GAT1 is the priming enzyme for the LARGE-dependent functional glycosylation of α-dystroglycan. eLife 3, 12109 (2014).
doi: 10.7554/eLife.03943
Inamori, K. et al. Dystroglycan function requires xylosyl- and glucuronyltransferase activities of LARGE. Science 335, 93–96 (2012).
pubmed: 22223806
pmcid: 3702376
doi: 10.1126/science.1214115
Briggs, D. C. et al. Structural basis of laminin binding to the LARGE glycans on dystroglycan. Nat. Chem. Biol. 12, 1–7 (2016).
doi: 10.1038/nchembio.2146
Goddeeris, M. M. et al. LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy. Nature 503, 136–140 (2013).
pubmed: 24132234
pmcid: 3891507
doi: 10.1038/nature12605
Dobson, C. M. et al. O-Mannosylation and human disease. Cell Mol. Life Sci. 70, 2849–2857 (2013).
pubmed: 23115008
doi: 10.1007/s00018-012-1193-0
pmcid: 23115008
de Paula, F. et al. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur. J. Hum. Genet 11, 923–930 (2003).
pubmed: 14647208
doi: 10.1038/sj.ejhg.5201066
pmcid: 14647208
Beltran-Valero de Bernabé, D. et al. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J. Med. Genet. 41, e61 (2004).
pubmed: 15121789
doi: 10.1136/jmg.2003.013870
pmcid: 15121789
Brockington, M. et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am. J. Hum. Genet. 69, 1198–1209 (2001).
pubmed: 11592034
pmcid: 1235559
doi: 10.1086/324412
Esapa, C. T. et al. Functional requirements for fukutin-related protein in the Golgi apparatus. Hum. Mol. Genet. 11, 3319–3331 (2002).
pubmed: 12471058
doi: 10.1093/hmg/11.26.3319
pmcid: 12471058
Esapa, C. T., McIlhinney, R. A. & Blake, D. J. Fukutin-related protein mutations that cause congenital muscular dystrophy result in ER-retention of the mutant protein in cultured cells. Hum. Mol. Genet. 14, 295–305 (2005).
pubmed: 15574464
doi: 10.1093/hmg/ddi026
pmcid: 15574464
Henriques, S. F., Gicquel, E., Marsolier, J. & Richard, I. Functional and cellular localization diversity associated with Fukutin-related protein patient genetic variants. Hum. Mutat. 40, 1874–1885 (2019).
pubmed: 31268217
doi: 10.1002/humu.23827
pmcid: 31268217
Brown, S., Santa Maria, J. P. & Walker, S. Wall teichoic acids of gram-positive bacteria. Annu. Rev. Microbiol. 67, 313–336 (2013).
pubmed: 24024634
doi: 10.1146/annurev-micro-092412-155620
pmcid: 24024634
Gerin, I. et al. ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto alpha-dystroglycan. Nat. Commun. 7, 11534 (2016).
pubmed: 27194101
pmcid: 4873967
doi: 10.1038/ncomms11534
Alhamidi, M. et al. Fukutin-related protein resides in the Golgi cisternae of skeletal muscle fibres and forms disulfide-linked homodimers via an N-terminal interaction. PLoS ONE 6, e22968 (2011).
pubmed: 21886772
pmcid: 3160285
doi: 10.1371/journal.pone.0022968
Krissinel, E. & Henrick, K. Inference of macromolecular assemblies from crystalline state. J. Mol. Biol. 372, 774–797 (2007).
pubmed: 17681537
doi: 10.1016/j.jmb.2007.05.022
pmcid: 17681537
Kubota, T. et al. Structural basis of carbohydrate transfer activity by human UDP-GalNAc: polypeptide α-N-acetylgalactosaminyltransferase (pp-GalNAc-T10). J. Mol. Biol. 359, 708–727 (2006).
pubmed: 16650853
doi: 10.1016/j.jmb.2006.03.061
pmcid: 16650853
Kuchta, K. et al. Comprehensive classification of nucleotidyltransferase fold proteins: identification of novel families and their representatives in human. Nucleic Acids Res. 37, 7701–7714 (2009).
pubmed: 19833706
pmcid: 2794190
doi: 10.1093/nar/gkp854
Dolatshad, N. F. et al. Mutated fukutin-related protein (FKRP) localises as wild type in differentiated muscle cells. Exp. Cell Res. 309, 370–378 (2005).
pubmed: 16055117
doi: 10.1016/j.yexcr.2005.06.017
pmcid: 16055117
Liang, W.-C. et al. Limb-girdle muscular dystrophy type 2I is not rare in Taiwan. Neuromuscul. Disord. 23, 675–681 (2013).
pubmed: 23800702
doi: 10.1016/j.nmd.2013.05.010
pmcid: 23800702
Lu, P. J. et al. Mutations alter secretion of fukutin-related protein. Biochim Biophys. Acta 1802, 253–258 (2010).
pubmed: 19900540
doi: 10.1016/j.bbadis.2009.10.016
pmcid: 19900540
Topaloglu, H. et al. FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. Neurology 60, 988–992 (2003).
pubmed: 12654965
doi: 10.1212/01.WNL.0000052996.14099.DC
pmcid: 12654965
Mercuri, E. et al. Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann. Neurol. 53, 537–542 (2003).
pubmed: 12666124
doi: 10.1002/ana.10559
Bassenden, A. V., Rodionov, D., Shi, K. & Berghuis, A. M. Structural analysis of the tobramycin and gentamicin clinical resistome reveals limitations for next-generation aminoglycoside design. ACS Chem. Biol. 11, 1339–1346 (2016).
pubmed: 26900880
doi: 10.1021/acschembio.5b01070
Cox, G., Stogios, P. J., Savchenko, A. & Wright, G. D. Structural and molecular basis for resistance to aminoglycoside antibiotics by the adenylyltransferase ANT(2″)-Ia. mBio 6, e02180–14–9 (2015).
doi: 10.1128/mBio.02180-14
Beard, W. A. & Wilson, S. H. Structure and mechanism of DNA polymerase β. Biochemistry 53, 2768–2780 (2014).
pubmed: 24717170
pmcid: 4018062
doi: 10.1021/bi500139h
Waterhouse, A. et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 46, W296–W303 (2018).
pubmed: 29788355
pmcid: 6030848
doi: 10.1093/nar/gky427
Imae, R. et al. CDP-glycerol inhibits the synthesis of the functional O-mannosyl glycan of α-dystroglycan. J. Biol. Chem. 293, 12186–12198 (2018).
pubmed: 29884773
pmcid: 6078450
doi: 10.1074/jbc.RA118.003197
Pak, J. E. & Rini, J. M. X-ray crystal structure determination of mammalian glycosyltransferases. Meth. Enzymol. 416, 30–48 (2006).
pubmed: 17113858
doi: 10.1016/S0076-6879(06)16003-6
pmcid: 17113858
Hiraki, M. et al. Development of an automated large-scale protein-crystallization and monitoring system for high-throughput protein-structure analyses. Acta Crystallogr. D. Biol. Crystallogr. 62, 1058–1165 (2006).
pubmed: 16929107
doi: 10.1107/S0907444906023821
pmcid: 16929107
Kabsch, W. XDS. Acta Crystallogr. D. Biol. Crystallogr. 66, 125–132 (2010).
pubmed: 20124692
pmcid: 2815665
doi: 10.1107/S0907444909047337
Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D. Biol. Crystallogr. 50, 760–763 (1994).
doi: 10.1107/S0907444994003112
Vonrhein, C., Blanc, E., Roversi, P. & Bricogne, G. Automated structure solution with autoSHARP. Methods Mol. Biol. 364, 215–230 (2007).
pubmed: 17172768
pmcid: 17172768
Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D. Biol. Crystallogr. 66, 486–501 (2010).
pubmed: 20383002
pmcid: 2852313
doi: 10.1107/S0907444910007493
Afonine, P. V. et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. D. Biol. Crystallogr. 68, 352–367 (2012).
pubmed: 22505256
pmcid: 3322595
doi: 10.1107/S0907444912001308
Holm, L. & Laakso, L. M. Dali server update. Nucleic Acids Res. 44, W351–W355 (2016).
pubmed: 27131377
pmcid: 4987910
doi: 10.1093/nar/gkw357
Bacot-Davis, V. R., Bassenden, A. V., Sprules, T. & Berghuis, A. M. Effect of solvent and protein dynamics in ligand recognition and inhibition of aminoglycoside adenyltransferase 2″-Ia. Protein Sci. 26, 1852–1863 (2017).
pubmed: 28734024
pmcid: 5563142
doi: 10.1002/pro.3224
Shimizu, N. et al. Software development for analysis of small-angle x-ray scattering data. AIP Conf. Proc. 1741, 050017 (2016).
doi: 10.1063/1.4952937
Konarev, P. V. et al. PRIMUS: a Windows PC-based system for small-angle scattering data analysis. J. Appl Crystallogr. 36, 1277–1282 (2003).
doi: 10.1107/S0021889803012779