structural biology

RESEARCH PORTFOLIO IN
CRYSTALLOGRAPHY  

MOLECULAR PATHOGENESIS OF A DISEASE

Human aspartylglucosaminidase cleaves the bond between asparagine and carbohydrate in lysosomes. Many mutations in the gene encoding for AGA result in inactive enzyme. This may lead to the severe mental retardation in humans (AGU disease). We have determined the crystal structure of AGA in collaboration with the group of Prof. Leena Peltonen-Palotie. The crystal structure showed that active native protein is heterotetrameric (dimer of heterodimer) and revealed binding of reaction product to the active site.

The enzyme is autocatalytically activated through oligomerization leading the formation of a new N-terminal residue (threonine) which is essential for catalysis. The disease causing mutations seem to affect oligomerization and autocatalysis resulting an inactive enzyme. Thus an enzyme which is maturated through autocatalysis is especially untolerant for mutations.

Oinonen C, Tikkanen R, Rouvinen J & Peltonen L: Three-dimensional structure of human lysosomal aspartylglucosaminidase, Nature Struct. Biol. 2 (1995) 1102-1108.

Tikkanen R, Riikonen A, Oinonen C, Rouvinen J & Peltonen L: Functional analyses of active site residues of human lysosomal aspartylglucosaminidase: implications for catalytic mechanism and autocatalytic activation, EMBO J.15 (1996) 2954-2960.

Tikkanen R, Peltola M, Oinonen C, Rouvinen J & Peltonen L: Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase, EMBO J. 16 (1997) 6684-6693.

Saarela J, Peltola M, Tikkanen R, Oinonen C, Jalanko A, Rouvinen J & Peltonen L: Activation and oligomerization of aspartylglucosaminidase, J. Biol. Chem. 273 (1998) 25320-25328.

Oinonen C & Rouvinen J: Structural comparison of Ntn-hydrolases. Protein Sci. 9 (2000) 2329-2337.

Saarela J, Laine M, Oinonen C, Jalanko A, Rouvinen J & Peltonen L: Characterization of molecular pathogenesis of a disease: Structural consequences of aspartylglucosaminuria mutations. Human Mol. Genet.10 (2001) 983-995.

Saarela J, Oinonen C, Jalanko A, Rouvinen J & Peltonen L: Autoproteolytic processing of aspartylglucosaminidase. Biochem J. 378 (2004) 363-371.