The X-ray Crystal Structures of Human {alpha}-Phosphomannomutase 1 Reveal the Structural Basis of Congenital Disorder of Glycosylation Type 1a

Journal Article · Sun Jan 01 04:00:00 EST 2006 · J. Biol. Chem.

DOI:https://doi.org/10.1074/jbc.M601505200· OSTI ID:914153

Silvaggi, N; Zhang, C; Lu, Z; Dai, J; Dunaway-Mariano, D; Allen, K

Carbohydrate-deficient glycoprotein syndrome type 1a (CDG-1a) is a congenital disease characterized by severe defects in nervous system development. It is caused by mutations in alpha -phosphomannomutase (of which there are two isozymes, {alpha}-PMM1 and {alpha}-PPM2). Here we report the X-ray crystal structures of human {alpha}-PMM1 in the open conformation, with and without the bound substrate, {alpha}-D-mannose 1-phosphate. {alpha}-PMM1, like most Haloalkanoic Acid Dehalogenase Superfamily (HADSF) members, consists of two domains, the cap and core, which open to bind substrate and then close to provide a solvent exclusive environment for catalysis. The substrate phosphate group is observed at a positively charged site of the cap domain, rather than at the core domain phosphoryl-transfer site defined by the D19 nucleophile and Mg{sup 2+} cofactor. This suggests that substrate binds first to the cap and then is swept into the active site upon cap closure. The orientation of the acid/base residue D21 suggests that {alpha}-PMM uses a different method of protecting the aspartylphosphate from hydrolysis than the HADSF member {beta}-phosphoglucomutase. It is hypothesized that the electrostatic repulsion of positive charges at the interface of the cap and core domains stabilizes {alpha}-PMM1 in the open conformation, and that the negatively charged substrate binds to the cap, thereby facilitating its closure over the core domain. The two isozymes {alpha}-PMM1 and {alpha}-PMM2 are shown to have a conserved active-site structure and to display similar kinetic properties. Analysis of the known mutation sites in the context of the structures reveals the genotype-phenotype relationship underlying CDG-1a.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 914153
• Report Number(s): BNL--78721-2007-JA
• Journal Information: J. Biol. Chem., Journal Name: J. Biol. Chem. Journal Issue: 21 Vol. 281; ISSN JBCHA3; ISSN 0021-9258
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CATALYSIS
CONGENITAL DISEASES
CRYSTAL STRUCTURE
DEFECTS
ELECTROSTATICS
GLYCOPROTEINS
HYDROLYSIS
KINETICS
MUTATIONS
NERVOUS SYSTEM
ORIENTATION
PHOSPHATES
RESIDUES
SOLVENTS
SUBSTRATES
national synchrotron light source