Basic Structure:

The overall quaternary structure of acitve AGA is heterotetrameric. The alpha chains are shown in red and green and beta chains are blue and purple. The alpha and beta subunits are packed together forming an "alpha-beta-beta-alpha sandwich." The 2 central beta sheets in the core of the domain are parallel each other and flanked by another beta sheet and an alpha helices on both sides. The first beta sheet has one parallel beta strand while the other strands are anitparallel. The second beta sheet contains four beta strands which are all antiparallel. "The loops connecting the secondary structural elements within the layer are on one side of the protein, but the loops connecting different layers of alpha helices or beta sheets are all on another side of the protein, providing loops for the acive site." The long c-terminus of the alpha chain is composed of one alpha helix which extends out of the core region. No disulphide bridges appear between the two heterodimers or between the alpha and beta chains but the nine cysteine residues of AGA form four disulfide bridges within the molecule . There are numerous hydrophobic and hydrogen bonds between the heterodimers but the van der Waals surface of the interface is flat. A His101 protrudes into the other heterodimer forming hydrogen bonds with the main chain nitrogen of Ile 208 and the carboxyl group of Asp238. (6) Correct folding of the subunits to higher-order structure is necessary for the formation of the active site.

Biological Significance:

A lysosomal accumulation disease known as aspartylglucoaminuria (AGU) in humans is caused by mutations in the gene for aspartylyglucosaminidase, located in the short arm of the fourth chromosome. "AGU is the only known lysosomal storage idsease caused by an amidase deficiency." Aspartylglucosaminuria is characterized by "severe mental retardation, periodic hyperactivity, broad facial features including the nose, short neck and asymmetry of the cranium. AGU is an autosomal recessive trait. Most of the mutations leading to AGU result in the misfolding and instability of the enzyme and do not affect the active site. Fisher found and reported mutations in AGA which caused the removal of a disulfide bridge whithin the molecule leading to a decrease in the flexibiltiy of the polypeptide chain.(7) "The majority of the mutations produce either a truncated polypeptide or cause defective folding and phosphorylation of the polypeptides."(1)