Structure
GLUD1 is a hexamer. The monomer unit has:
- N-terminal Glu-BD(Binding domain) that is composed mostly of β-strands.
- NAD-BD - can bind either NAD+ or NADP+.
- 48-residue antenna-like projection that extends from the top of each NAD-BD. The antenna consists of an ascending helix and a descending random coil strand that contains a small α-helix toward the C-terminal end of the strand.
NAD-BD sits on the top of Glu-BD. NAD-BD and Glu-BD form the catalytic cleft. During substrate binding, the NAD-BD moves significantly. This movement has two components, rotating along the long axis of a helix at the back of the NAD-BD, called "the pivot helix", and twisting about the antenna in a clockwise fashion. A comparison of the open and closed conformations of GLUD1 reveals changes in the small helix of the descending strand of the antenna, which seems to recoil as the catalytic cleft opens. Closure of one subunit is associated with distortion of the small helix of the descending strand that is pushed into the antenna of the adjacent subunit. R496 is located on this small helix (see Mutations).
The core structure of the hexamer is a stacked dimer of trimers. Glu-BDs of the monomers are mainly responsible in the build up of the core. The relative position of the monomers is such that the rotation about the pivot helix in each monomer is not restricted. The antennae from three subunits within the trimers wrap around each other and undergo conformational changes as the catalytic cleft opens and closes. The antenna serves as an intersubunit communication conduit during negative cooperativity and allosteric regulation.
Alignment of GLUD1 from various sources, shows that the antenna probably evolved in the protista prior to the formation of purine regulatory sites. This suggests that there is some selective advantage of the antenna itself and that animals evolved new functions for GLUD1 through the addition of allosteric regulation.
GLUD1 can form long fibers by end to end association of the hexamers. The polimerization is unrelated to the catalytic activity, but probably has an important role such as formation of multienzyme comolexes.
GLUD1 has two co-enzyme binding sites: one in the NAD-BD that is able to bind ether NAD+ or NADP+ and is directly involved in the catalytic process, and a second one, that has regulatory function, lying directly under the pivot helix, that can bind ADP, NAD+, or NADH, but does not bind NADPH well.
Read more about this topic: Glutamate Dehydrogenase 1
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