Structures and Mechanisms of Protein Remodeling Machines

Cdc48 AAA ATPase unfolding a protein substrate.

When a cellular protein has done its job or lost its utility, it should be removed, recycled, or remodeled. These tasks are performed by members of the ubiquitous family of AAA ATPases (ATPases associated with diverse cellular activities) that convert the energy of ATP hydrolysis into mechanical forces that can unfold protein aggregates, degrade unwanted proteins, and remodel protein complexes. To learn how AAA ATPases unfold proteins, Hill, Shen, Sundquist, and colleagues used electron cryomicroscopy to determine structures and elucidate the common mechanisms of several different AAA ATPases in complex with their polypeptide substrates. The team found that each enzyme forms a hexameric ring shaped like a lock washer, with the substrate in the central pore.


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Structural basis of protein translocation by the Vps4-Vta1 AAA ATPase. Monroe N, Han H, Shen PS, Sundquist WI, Hill CP. Elife. 2017 Apr;6. pii: e24487.

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The AAA ATPase Vps4 binds ESCRT-III substrates through a repeating array of dipeptide-binding pockets. Han H, Monroe N, Sundquist WI, Shen PS, Hill CP. Elife. 2017 Nov;6. pii: e31324.

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Structure of Vps4 with circular peptides and implications for translocation of two polypeptide chains by AAA+ ATPases. Han H, Fulcher JM, Dandey VP, Iwasa JH, Sundquist WI, Kay MS, Shen PS, Hill CP. Elife. 2019 Jun;8. pii: e44071.

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Structure of the Cdc48 segregase in the act of unfolding an authentic substrate. Cooney I, Han H, Stewart MG, Carson RH, Hansen DT, Iwasa JH, Price JC, Hill CP, Shen PS. Science. 2019 Aug;365(6452):502.

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University of Utah Health: Researchers Solve How Cells Unfold Proteins