. Structure of PINK1 in complex with its substrate ubiquitin. Nature. 2017 Oct 30; PubMed.


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  1. Among the proteins implicated in the pathogenesis of Parkinson’s disease, the mitochondrial kinase PINK1 is undoubtedly one of the most eclectic, and over the past decade it has been clearly demonstrated that its neuroprotective activity unravels through a multitude of distinct mechanisms and pathways, within and outside mitochondria. These include the pro-survival phosphorylation of mitochondrial and anti-apoptotic proteins (such as TRAP1, NdufA10 and Bcl-xL), as well as a pivotal role in the regulation of mitophagy, exerted through two parallel mechanisms: on the one hand, the recruitment of Beclin1 to the mitochondria-associated membranes to form autophagosomes, and on the other hand, phosphorylation and recruitment of both parkin and ubiquitin onto the surface of damaged mitochondria to “process” them for mitophagic digestion. Yet the structure of PINK1 has remained elusive for more than a decade, hampering a deeper knowledge of PINK1 interaction with its substrates and, most importantly, of the different impact of distinct PD-related mutations on the various PINK1 functions.

    Now, the structure of Pediculus humanus corporis (Ph)PINK1 in complex with its substrate ubiquitin has been finally revealed in this study led by David Komander. This is a very important work for a number of reasons. Firstly, the authors demonstrated that (Ph)PINK1 does not phosphorylate ubiquitin in its common conformation, but specifically binds to a recently described but less represented “C-terminally retracted” conformation of ubiquitin. Secondly, they revealed some unique peculiarities of PINK1, such as the structure of the C-terminus domain, a region with no homologies with other proteins that was long known to modulate PINK1 catalytic activity, and the presence of three unique insertions in the kinase N-lobe, of which insertion-3 seems to be the most relevant to enable kinase activity (of note, this was also reported in the recent study on the structure of Tribolium castaneum PINK1, by Kumar and collaborators). Finally, Komander’s group was able to map most of the PINK1 mutations causative of PD on the (Ph)PINK1 structure, and showed that distinct mutations had variable effects on either protein folding, substrate binding, autophosphorylation, or complete kinase activity. This finding makes sense of previous observations noting a different impact of various PINK1 mutations on the protein’s many functions. For instance, we reported that PINK1W437X, a deletion mutant which entirely lacks the C-terminus domain and shows increased autophosphorylation activity, had impaired ability to bind Beclin1 and to enhance autophagy, while this was not observed for PINK1G309D, a mutant with defective kinase activity but unaltered ability to bind Beclin1 (Michiorri et al., 2010). In this light, the definition of the structure of PINK1 (albeit not yet that of the human protein) opens novel intriguing perspectives to better characterize its many interactions, and to establish whether some of these interactions may not necessarily implicate phosphorylation of the substrate, as seems to be the case for Beclin1. 


    . The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell Death Differ. 2010 Jun;17(6):962-74. PubMed.

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