SIAH1, E3 Ubiquitin Ligase

Seven in absentia homolog 1 (SIAH-1) is a member of the RING-finger-containing E3 ubiquitin ligases. Alpha-synuclein and synphilin-1 are substrates of SIAH-1. Both proteins are involved in the development of Parkinson's disease (PD). Mutations in Parkin, another E3 ubiquitin ligase which ubiquinates synphilin-1 and glycosylated alpha-synuclein, have been defined as a major cause of autosomal recessive PD. The role of SIAH-1 in PD is highlighted by the fact that SIAH-1 is a component of the Lewy bodies and plays a role in apoptosis caused by nitric oxide (NO) induced oxidative stress. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) a classic glycolytic enzyme, and multi-functional protein. GAPDH plays role as a mediator for cell death. GAPDH translocates to the nucleus under a variety of stressors/conditions, most of which are associated with oxidative stress. Sequential steps lead to nuclear translocation of GAPDH during cell death; 1] a catalytic cysteine in GAPDH (C150 in rat GAPDH) is S-nitrosylated by nitric oxide (NO) which is generated from inducible nitric oxide synthase (iNOS) and/or neuronal NOS (nNOS); 2] the modified GAPDH becomes capable of binding with Siah1, an E3 ubiquitin ligase, and stabilizes it;3] the GAPDH-Siah protein complex translocates to the nucleus, dependent on Siah1's nuclear localization signal, and degrades Siah1's substrates in the nucleus, which results in cytotoxicity.