AI Article Synopsis
- The AAA-ATPase VCP/p97/Cdc48 facilitates protein unfolding by threading substrates through its pore, raising questions about how it recognizes and processes different substrates.
- Researchers discovered that p97, along with the adapter p37, binds to an internal recognition site on the inhibitor-3 (I3) protein and threads a loop into the pore to remove I3 from protein phosphatase-1 (PP1).
- Key mutations in the recognition site hinder I3 processing, while the terminal regions of I3 are not essential for this process, highlighting the adaptable nature of p97 in its substrate interactions.
Article Abstract
The AAA-ATPase VCP/p97/Cdc48 unfolds proteins by threading them through its central pore, but how substrates are recognized and inserted into the pore in diverse pathways has remained controversial. Here, we show that p97, with its adapter p37, binds an internal recognition site (IRS) within inhibitor-3 (I3) and then threads a peptide loop into its channel to strip I3 off protein phosphatase-1 (PP1). Of note, the IRS is adjacent to the prime interaction site of I3 to PP1, and IRS mutations block I3 processing both in vitro and in cells. In contrast, amino- and carboxy-terminal regions of I3 are not required, and even circularization of I3 does not prevent I3 processing. This was confirmed by an in vitro Förster resonance energy transfer assay that allowed kinetic analysis of the reaction. Thus, our data uncover how PP1 is released from its inhibitory partner for activation and demonstrate a remarkable plasticity in substrate threading by p97.
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| http://dx.doi.org/10.1038/s41594-021-00684-5 | DOI Listing |
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