Literature summary for 3.2.1.46 extracted from

Deane, J.E.; Graham, S.C.; Kim, N.N.; Stein, P.E.; McNair, R.; Cachon-Gonzalez, M.B.; Cox, T.M.; Read, R.J.
Insights into Krabbe disease from structures of galactocerebrosidase (2011), Proc. Natl. Acad. Sci. USA, 108, 15169-15173.

Application

Application	Comment	Organism
medicine	mutations involved in Krabbe's disease are widely distributed throughout the protein. Mutations that are likely to result in severe misfolding include E114K and S257F in the TIM barrel, L364R and W410G in the beta-sandwich domain, and G537R and L629R in the lectin domain. Mutation E215K is exposed on the surface of the TIM barrel. The mutation confers an opposite charge on the same face as the substrate-binding pocket suggesting that the mechanism of disease for this mutation will involve the perturbation of a binding face for an activating factor. Residue P302 that is found on the surface of GALC very close to the substrate-binding pocket is mutated to arginine in Krabbe's disease. The beta-sandwich domain of a long loop forms an integral part of the substrate-binding site. R380 at the tip of this loop directly binds the galactose molecule in the active site, its mutation to tryptophan or leucine leads to severe infantile Krabbe's disease	Mus musculus

Crystallization (Commentary)

Crystallization (Comment)	Organism
crystal structures of GALC and the GALC-D-galactose product complex, to 2.1 and 2.4 A resolution, respectively. The overall fold comprises a central triosephosphate isomerase barrel, a beta-sandwich domain, and a lectin domain. The overall fold of GALC is unchanged upon galactose binding, the core of the binding pocket being formed by the long loops on the C-terminal face of the TIM barrel. Loops from both the beta-sandwich and lectin domains also contribute to the substrate-binding pocket, and mutations involved in Krabbe's disease are widely distributed throughout the protein	Mus musculus

Crystallization (Comment)

Organism

crystal structures of GALC and the GALC-D-galactose product complex, to 2.1 and 2.4 A resolution, respectively. The overall fold comprises a central triosephosphate isomerase barrel, a beta-sandwich domain, and a lectin domain. The overall fold of GALC is unchanged upon galactose binding, the core of the binding pocket being formed by the long loops on the C-terminal face of the TIM barrel. Loops from both the beta-sandwich and lectin domains also contribute to the substrate-binding pocket, and mutations involved in Krabbe's disease are widely distributed throughout the protein

Mus musculus

Protein Variants

Protein Variants	Comment	Organism
E114K	residue in TIM barrel, mutation is likely to result in severe misfolding, crystallization data	Mus musculus
E215K	residue is exposed on the surface of the TIM barrel, mutation confers an opposite charge on the same face as the substrate-binding pocket, crystallization data	Mus musculus
G537R	resiude in lectin domain, mutation is likely to result in severe misfolding, crystallization data	Mus musculus
L364R	resiude in beta-sandwich, mutation is likely to result in severe misfolding, crystallization data	Mus musculus
L629R	resiude in lectin domain, mutation is likely to result in severe misfolding, crystallization data	Mus musculus
S257F	resiude in TIM barrel, mutation is likely to result in severe misfolding, crystallization data	Mus musculus
W410G	resiude in beta-sandwich, mutation is likely to result in severe misfolding, crystallization data	Mus musculus

Organism

Organism	UniProt	Comment	Textmining
Mus musculus	P54818	-	-