Detailed Dissection of UBE3A-Mediated DDI1 Ubiquitination

Discussion Poly-ubiquitinated proteins targeted for degradation might be recognized directly by proteasomal receptors or by proteasomal shuttling proteins. The first shuttling proteins – Ddi1, Rad23 and Dsk2 – were identified and characterized in Saccharomyces cerevisiae (Lambertson et al., 1999; Kaplun et al., 2005). Proteasomal shuttles contain an N-terminal ubiquitin-like (UBL) domain that interacts with the 26S proteasome (Finley, 2009), and a C-terminal ubiquitin-binding domain domain (UBD) that binds to ubiquitin or poly-ubiquitin chains (Bertolaet et al., 2001). When ubiquitinated, substrates are captured by the UBD domain, whereas the UBL domain binds to UBL receptors of the proteasome, delivering the substrates for degradation (Finley, 2009). Yeast Ddi1 and Ddi1-like shuttling proteins (e.g., Ddi2) show unique properties among canonical proteasomal shuttles. On the one hand, their UBL domain is able to bind ubiquitin (Nowicka et al., 2015), and despite having a ubiquitin-like fold, it does not interact or very weakly interacts with typical UBL receptors, including Rpn10 (Zhang et al., 2009) and Rpn1 (Rosenzweig et al., 2012). On the other hand, human DDI1 and Ddi1-like proteins from vertebrates lack the UBA domain (a type of UBD), but instead interact with ubiquitin through their UBL domain (Nowicka et al., 2015) or the ubiquitin-interacting motif (UIM) in the case of Ddi1-like proteins (Nowicka et al., 2015; Sivá et al., 2016). In line with thi...
Source: Frontiers in Physiology - Category: Physiology Source Type: research