Developing Practical Therapeutic Strategies that Target Protein SUMOylation

Abstract

Post-translational modification by small ubiquitin-like modifier (SUMO) has emerged as a global mechanism for the control and integration of a wide variety of biological processes through the regulation of protein activity, stability and intracellular localization. As SUMOylation is examined in greater detail, it has become clear that the process is at the root of several pathologies including heart, endocrine, and inflammatory disease, and various types of cancer. Moreover, it is certain that perturbation of this process, either globally or of a specific protein, accounts for many instances of congenital birth defects. In order to be successful, practical strategies to ameliorate conditions due to disruptions in this post-translational modification will need to consider the multiple components of the SUMOylation machinery and the extraordinary number of proteins that undergo this modification.

Keywords: SENP protease; SUMO; SUMO ligase; cancer; congenital birth defects; heart development; heart failure; neural tube; neurodegenerative disease; spina bifida..

Fig. (1)

The SUMO pathway. SUMO precursor polypeptide undergoes cleavage by a SENP protease to reveal a C-terminal di-glycine sequence (1) which is the substrate for the ATP-dependent formation of the covalent intermediate with the E1 SUMO activating enzyme (2). The SUMO polypeptide is transferred to the E2 SUMO conjugating enzyme (3). In most cases, an E3 SUMO ligase brings together the E2 enzyme and substrate protein (4) to promote the transfer SUMO to the target (5). SUMO moieties can be removed by members of the SENP family of proteases (6).