Zooming into the structure-function of RING finger proteins for anti-cancer therapeutic applications

Abstract

Cancer is one of the most common and widely diagnosed diseases worldwide. With an increase in prevalence and incidence, many studies in cancer biology have been looking at the role pro-cancer proteins play. One of these proteins is the Really Interesting New Gene (RING), which has been studied extensively due to its structure and functions such as apoptosis, neddylation, and its role in ubiquitination. The RING domain is a cysteine-rich domain known to bind Cysteine and Histidine residues. It also binds two zinc ions that help stabilize the protein in various patterns, often with a 'cross-brace' topology. Different RING finger proteins have been studied and found to have suitable targets for developing anti-cancer therapeutics. These identified candidate proteins include Parkin, COP1, MDM2, BARD1, BRCA-1, PIRH2, c-CBL, SIAH1, RBX1 and RNF8. Inhibiting these candidate proteins provides opportunities for shutting down pathways associated with tumour development and metastasis.

Keywords: Anti-cancer therapeutics; Parkin; RING finger proteins; neddylation; ubiquitination.

Figure 1

A model representing the various targets of RING finger proteins for use in cancer therapeutics. (1) Tumour development can lead directly to metastasis. Metastasis can occur due to overexpression of certain RING finger proteins such as RBX1; (2) Inducing of certain RING finger proteins such as CBL will lead to neddylation of the proteins that interact with them; (3) Neddylation causes a conformational change to occur and recruit ubiquitin; (4) And ultimately lead to proteasomal degradation; (5) Or can lead to apoptosis, which leads to the inhibition of tumour development; (6) Inducing of RING finger proteins such as Parkin; (7) This will lead to ubiquitination of the proteins that interact with them and ultimately lead to proteasomal degradation; (8) Or can also lead to mitophagy through a joint autophagic machinery; (9) The induction of Parkin can also lead to apoptosis; (10) Inhibition of RING finger proteins such as RBX1; (11) Will cause the inhibition of E3 activity such as ubiquitination; (12) But does lead to apoptosis and thus inhibiting metastasis.