Structure and Function of p97 and Pex1/6 Type II AAA+ Complexes.

Paul Saffert,Cordula Enenkel,Petra Wendler

doi:10.3389/fmolb.2017.00033

Paul Saffert, Cordula Enenkel + Show 1 more

Open Access

https://doi.org/10.3389/fmolb.2017.00033

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Abstract

Protein complexes of the Type II AAA+ (ATPases associated with diverse cellular activities) family are typically hexamers of 80–150 kDa protomers that harbor two AAA+ ATPase domains. They form double ring assemblies flanked by associated domains, which can be N-terminal, intercalated or C-terminal to the ATPase domains. Most prominent members of this family include NSF (N-ethyl-maleimide sensitive factor), p97/VCP (valosin-containing protein), the Pex1/Pex6 complex and Hsp104 in eukaryotes and ClpB in bacteria. Tremendous efforts have been undertaken to understand the conformational dynamics of protein remodeling type II AAA+ complexes. A uniform mode of action has not been derived from these works. This review focuses on p97/VCP and the Pex1/6 complex, which both structurally remodel ubiquitinated substrate proteins. P97/VCP plays a role in many processes, including ER- associated protein degradation, and the Pex1/Pex6 complex dislocates and recycles the transport receptor Pex5 from the peroxisomal membrane during peroxisomal protein import. We give an introduction into existing knowledge about the biochemical and cellular activities of the complexes before discussing structural information. We particularly emphasize recent electron microscopy structures of the two AAA+ complexes and summarize their structural differences.

Highlights

The conversion of chemical energy in the form of nucleotide triphosphates into mechanical energy is a process utilized by all living cells and associated with a large variety of cellular functions
It appears that the type of nucleotide bound to NBD1 has a vital role in the overall ATPase activity
Side-by-side comparison of the ATPγS bound p97 and Pex1/6 electron microscopy (EM) structures of similar resolution shows that the outer diameter of the nucleotide-binding domain (NBD) rings is almost identical (Figure 3A)

Summary

INTRODUCTION

The conversion of chemical energy in the form of nucleotide triphosphates into mechanical energy is a process utilized by all living cells and associated with a large variety of cellular functions. Proteins of the AAA+ superfamily are often essential parts of such molecular machines They catalyze the hydrolysis of ATP to ADP resulting in mechanical work on a substrate molecule. All AAA+ have a structurally conserved nucleotide-binding domain (NBD) in common, usually comprising 200–250 amino acids (AA), which is essentially responsible for ATP binding and subsequent hydrolysis (Wendler et al, 2012). All AAA+ NBDs share a conserved Rossmann fold domain with a 51432 topology of the central β-sheet and a C-terminal alpha helical domain. They contain multiple conserved features including the Walker A motif, Walker B motif (Walker et al, 1982) and the second region of homology (SRH) (Swaffield et al, 1992). We would like to refer the interested reader to these publications for an in-depth coverage of these topics

PROTEIN COMPLEX

Binding partners

Findings

STRUCTURAL DIFFERENCES BETWEEN