Year: 2024
Type: article
Abstract: AAA+ proteolytic machines unfold proteins before degrading them. Here, we present cryoEM structures of ClpXP-substrate complexes that reveal a postulated but heretofore unseen intermediate in substrate unfolding/degradation. A ClpX hexamer draws natively folded substrates tightly against its axial channel via interactions with a fused C-terminal degron tail and ClpX-RKH loops that flexibly conform to the globular substrate. The specific ClpX-substrate contacts observed vary depending on the substrate degron and affinity tags, helping to explain ClpXP’s ability to unfold/degrade a wide array of different cellular substrates. Some ClpX contacts with native substrates are enabled by upward movement of the seam subunit in the AAA+ spiral, a motion coupled to a rearrangement of contacts between the ClpX unfoldase and ClpP peptidase. Our structures additionally highlight ClpX’s ability to translocate a diverse array of substrate topologies, including the co-translocation of two polypeptide chains. AAA proteases must unfold substrates before degradation. Here the authors report cryo-EM structures to visualize how these machines achieve this by pulling the substrate tightly against their narrow axial channel and encircling the substrate’s folded domain using only the unfoldase’s flexible loops.
Source: Nature Communications
Language: English
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: Tools to determine and analyze the structures of molecular machines in motion, G2785234099, G3581519619, G3767986365, G5827388610, Structure and function of ClpXP, G6671297155, G7045101289, G7753783864, CAREER: Developing novel structural techniques to untangle bacterial ribosome biogenesis, G9000274300
OpenAlex ID: W4404164302