Crystal Structure of Human β-galactosidase: Structural Basis of Gm1 Gangliosidosis and Morquio B Diseases

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Dec 1

PMID 22128166

Citations 55

Authors

Umeharu Ohto

Kimihito Usui

Toshinari Ochi

Kenjiro Yuki

Yoshinori Satow

Toshiyuki Shimizu

Affiliations

Soon will be listed here.

Abstract

G(M1) gangliosidosis and Morquio B are autosomal recessive lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the lysosomal enzyme β-d-galactosidase (β-Gal), which lead to accumulations of the β-Gal substrates, G(M1) ganglioside, and keratan sulfate. β-Gal is an exoglycosidase that catalyzes the hydrolysis of terminal β-linked galactose residues. This study shows the crystal structures of human β-Gal in complex with its catalytic product galactose or with its inhibitor 1-deoxygalactonojirimycin. Human β-Gal is composed of a catalytic TIM barrel domain followed by β-domain 1 and β-domain 2. To gain structural insight into the molecular defects of β-Gal in the above diseases, the disease-causing mutations were mapped onto the three-dimensional structure. Finally, the possible causes of the diseases are discussed.

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References

. The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr. 1994; 50(Pt 5):760-3. DOI: 10.1107/S0907444994003112. View

Montanier C, Lammerts van Bueren A, Dumon C, Flint J, Correia M, Prates J . Evidence that family 35 carbohydrate binding modules display conserved specificity but divergent function. Proc Natl Acad Sci U S A. 2009; 106(9):3065-70. PMC: 2651348. DOI: 10.1073/pnas.0808972106. View

Okumiya T, Sakuraba H, Kase R, Sugiura T . Imbalanced substrate specificity of mutant beta-galactosidase in patients with Morquio B disease. Mol Genet Metab. 2003; 78(1):51-8. DOI: 10.1016/s1096-7192(02)00199-3. View

Jacobson R, Zhang X, DuBose R, Matthews B . Three-dimensional structure of beta-galactosidase from E. coli. Nature. 1994; 369(6483):761-6. DOI: 10.1038/369761a0. View

Brunetti-Pierri N, Scaglia F . GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab. 2008; 94(4):391-396. DOI: 10.1016/j.ymgme.2008.04.012. View

Morreau H, Galjart N, Gillemans N, Willemsen R, van der Horst G, dAzzo A . Alternative splicing of beta-galactosidase mRNA generates the classic lysosomal enzyme and a beta-galactosidase-related protein. J Biol Chem. 1989; 264(34):20655-63. View

Rojas A, Nagem R, Neustroev K, Arand M, Adamska M, Eneyskaya E . Crystal structures of beta-galactosidase from Penicillium sp. and its complex with galactose. J Mol Biol. 2004; 343(5):1281-92. DOI: 10.1016/j.jmb.2004.09.012. View

Yamamoto Y, Hake C, Martin B, Kretz K, Ahern-Rindell A, Naylor S . Isolation, characterization, and mapping of a human acid beta-galactosidase cDNA. DNA Cell Biol. 1990; 9(2):119-27. DOI: 10.1089/dna.1990.9.119. View

Hoogeveen A, Verheijen F, GALJAARD H . The relation between human lysosomal beta-galactosidase and its protective protein. J Biol Chem. 1983; 258(20):12143-6. View

10.

Yamamoto Y, Fujie M, Nishimura K . The interrelation between high- and low-molecular-weight forms of GM1-beta-galactosidase purified from porcine spleen. J Biochem. 1982; 92(1):13-21. DOI: 10.1093/oxfordjournals.jbchem.a133910. View

11.

DISTLER J, JOURDIAN G . The purification and properties of beta-galactosidase from bovine testes. J Biol Chem. 1973; 248(19):6772-80. View

12.

Wallace A, Laskowski R, Thornton J . LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng. 1995; 8(2):127-34. DOI: 10.1093/protein/8.2.127. View

13.

Thompson J, Higgins D, Gibson T . CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994; 22(22):4673-80. PMC: 308517. DOI: 10.1093/nar/22.22.4673. View

14.

Asp N, Dahlqvist A . Human small intestine -galactosidases: specific assay of three different enzymes. Anal Biochem. 1972; 47(2):527-38. DOI: 10.1016/0003-2697(72)90147-9. View

15.

Hoogeveen A, Reuser A, Kroos M, GALJAARD H . GM1-gangliosidosis. Defective recognition site on beta-galactosidase precursor. J Biol Chem. 1986; 261(13):5702-4. View

16.

Oshima A, Yoshida K, Shimmoto M, Fukuhara Y, Sakuraba H, Suzuki Y . Human beta-galactosidase gene mutations in morquio B disease. Am J Hum Genet. 1991; 49(5):1091-3. PMC: 1683264. View

17.

McCarter J, Withers S . Mechanisms of enzymatic glycoside hydrolysis. Curr Opin Struct Biol. 1994; 4(6):885-92. DOI: 10.1016/0959-440x(94)90271-2. View

18.

Murshudov G, Vagin A, Dodson E . Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997; 53(Pt 3):240-55. DOI: 10.1107/S0907444996012255. View

19.

Skalova T, Dohnalek J, Spiwok V, Lipovova P, Vondrackova E, Petrokova H . Cold-active beta-galactosidase from Arthrobacter sp. C2-2 forms compact 660 kDa hexamers: crystal structure at 1.9A resolution. J Mol Biol. 2005; 353(2):282-94. DOI: 10.1016/j.jmb.2005.08.028. View

20.

Van der Spoel A, Bonten E, dAzzo A . Processing of lysosomal beta-galactosidase. The C-terminal precursor fragment is an essential domain of the mature enzyme. J Biol Chem. 2000; 275(14):10035-40. DOI: 10.1074/jbc.275.14.10035. View