Fig. 1. Parkin is a dual function E3 ligase. Different outcomes result from Parkin's dual function polyubiquitin chain formation. K48-linked poly-ubiquitination is responsible for substrate degradation via the proteasome. K63-linked polyubiquitination of substrates may be involved in Lewy Body formation. Reproduced with permission (Lim et al., 2006)
parkin can mediate the degradation of syn-philin-1 (Lim et al., 2005a). Consistent with our findings, Madura and co-workers also demonstrated recently the ability of parkin to assemble both K48- and K63-linked chains under different conditions (Doss-Pepe et al., 2005). Thus parkin appears to function as a dual function ubiquitin ligase (Fig. 1). The dual specific activity of parkin is apparently governed by members of the E2s it recruits. Parkin apparently interacts with the E2 complex composing of UbcH13 and Uevla in the assembly of K63-linked chain (Doss-Pepe et al., 2005). The UbcH13/Uev1a heterodi-mer is the only E2 enzyme that is known to mediate K63-linked polymerization of ubi-quitin. On the other hand parkin utilizes UbcH7 and UbcH8 for its degradative function (von Coelln et al., 2004a). It is not clear what governs the extrinsic or intrinsic factors that determine parkin's choice of E2. Thus, parkin may play important roles in the degradation and sequestration of toxic proteins in PD.
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