Protein SUMOylation in neuropathological conditions

Abstract

Small ubiquitin-related modifier (SUMO) proteins are approximately 11 kDa proteins that can be covalently conjugated to lysine residues in defined target proteins. The resultant post-translational modification, SUMOylation, is vital for the viability of mammalian cells and regulates, among other things, a range of essential nuclear processes. It has become increasingly apparent in recent years that SUMOylation also serves multiple functions outside the nucleus and that it plays a critical role in the regulation of neuronal integrity and synaptic function. In particular, dysfunction of the SUMOylation pathway has been implicated in the molecular and cellular dysfunction associated with neurodegenerative and psychiatric disorders. Here, we outline current knowledge of the SUMO pathway and discuss the growing evidence for its involvement in multiple neurodegenerative disorders, with a view to highlighting the potential of the SUMO pathway as a putative drug target.

Figure 1

Alignment of mature ubiquitin and SUMO protein sequences. Residues conserved across all four proteins are shown in red. Residues conserved across all SUMO members are shown in turquoise. The conjugatable C-terminal diglycine motif is indicated. Due to the controversy over whether it is a functional protein modifier, SUMO4 is not shown.

Figure 2

The SUMO pathway. SUMO is transcribed as an inactive precursor, which is cleaved by members of the SENP (sentrin-specific protease) family to expose a C-terminal diglycine motif. This mature form of SUMO is then activated by the ATP-dependent formation of a thioester bond with the active site of the E1 enzyme, a heterodimer of SUMO-activating enzyme (SAE)1 and SAE2. The activated SUMO is then passed to the active site cysteine of the E2 conjugating enzyme, Ubc9, which then catalyzes the transfer of SUMO to the target protein, often in conjunction with an E3 enzyme. The SUMOylated protein then displays phenotypic differences to the unmodified form, until the SUMO tag is removed, again by the SENP family of proteases, releasing the unmodified target protein (not shown), and mature SUMO, which can then undergo further rounds of conjugation to target proteins.