IntroductionĪTPases associated with diverse cellular activities (AAA proteins) utilize the energy of ATP hydrolysis to facilitate numerous functions in the cell, such as degrading proteins ( Pickart and Cohen, 2004), dissolving protein aggregates ( Sanchez and Lindquist, 1990), or moving proteins across membranes ( Ye et al., 2001 Gardner et al., 2018). We present a comprehensive model of Msp1’s mechanism, which follows general architectural principles established for other AAA proteins yet specializes Msp1 for its unique role in membrane protein extraction. Elements at the intersubunit interfaces coordinate ATP hydrolysis with the subunits’ positions in the spiral. There, a tight web of aromatic amino acids grips the substrate in a sequence-promiscuous, hydrophobic milieu. A singular hydrophobic substrate recruitment site is exposed at the spiral’s seam, which we propose positions the substrate for entry into the pore. Akin to other AAA proteins, Msp1 forms hexameric spirals that translocate substrates through a central pore. To address this question, we solved cryo-EM structures of Msp1-substrate complexes at near-atomic resolution. How Msp1 selects its substrates and firmly engages them during the energetically unfavorable extraction process remains a mystery.
The AAA protein Msp1 extracts mislocalized tail-anchored membrane proteins and targets them for degradation, thus maintaining proper cell organization.
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