Transglutaminase activation in neurodegenerative diseases

Abstract

The following review examines the role of calcium in promoting the in vitro and in vivo activation of transglutaminases in neurodegenerative disorders. Diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease exhibit increased transglutaminase activity and rises in intracellular calcium concentrations, which may be related. The aberrant activation of transglutaminase by calcium is thought to give rise to a variety of pathological moieties in these diseases, and the inhibition has been shown to have therapeutic benefit in animal and cellular models of neurodegeneration. Given the potential clinical relevance of transglutaminase inhibitors, we have also reviewed the recent development of such compounds.

Figure 1. Closed state of TG 2

The secondary structure of the closed form of TG 2 (PDB 1KV3) is rendered as a ribbon inside the molecular surface of the protein with an associated GDP depicted in a ball-and-stick configuration.

Figure 2. Active state of TG 2 with exposed active site

The secondary structure of the unfolded active form of TG 2 (PDB 2Q3Z) is rendered as a ribbon inside the molecular surface of the protein.

Figure 3. Calcium-binding site 1 in TG 3

The coordinating residues for the calcium bound to site 1 of TG 3 (PDB 1L9N) are rendered as a ribbon, and residues Ala²²¹, Asn²²⁴, Asn²²⁶ and Asp₂₂₈ are shown in a ball-and-stick configuration around the calcium. The molecular surface of the protein is shown in yellow. It should be noted that the calcium at this site is almost fully enveloped inside the surface of the protein.

Figure 4. Calcium-binding site 2 in TG 3

The coordinating residues for the calcium bound to site 2 of TG 3 in both the calcium bound (PDB 1L9N) and calcium free (PDB 1L9M) are shown. The backbone of the bound state is rendered in blue and the free state is rendered in green, as are the atoms with the calcium rendered as in CPK. The residues involved are Asn³⁹³, Ser⁴¹⁵, Glu⁴⁴³ and Glu⁴⁴⁸. It should be noted that there is significant motion of Asn³⁹³ and Glu⁴⁴³ upon calcium binding.

Figure 5. Calcium-binding site 3 in TG 3

The coordinating residues for the calcium bound to site 3 of TG 3 in both the calcium-bound (PDB 1L9N) and calcium-free state (PDB 1L9M) are shown. The backbone of the bound state is rendered in blue and the free state is rendered in green, as are the atoms with the calcium rendered as in CPK. The residues involved are Asp³⁰¹, Asp³⁰³, Asn³⁰⁵, Ser³⁰⁷ and Asp³²⁴. Of note, there is significant motion of Asp³²⁴ in this binding site, which in the free state is significantly displaced from its position in the bound state.