Sculpting the Proteome with AAA+ Proteases and Disassembly Machines
TL;DR: Exciting progress has been made in understanding how AAA(+) machines recognize specific proteins as targets and then carry out ATP-dependent dismantling of the tertiary and/or quaternary structure of these molecules during the processes of protein degradation and the disassembly of macromolecular complexes.
About: This article is published in Cell.The article was published on 2004-10-01 and is currently open access. It has received 460 citations till now. The article focuses on the topics: Protein degradation.
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TL;DR: Recent reports describe the removal of aggregates from the cytosol; reveal mechanisms for protein quality control in the endoplasmic reticulum; and provide new insight into two classes of molecular chaperones, the Hsp70 system and the AAA+ (Hsp100) unfoldases.
1,467 citations
TL;DR: The structural organization of AAA+ proteins, the conformational changes they undergo, the range of different reactions they catalyse, and the diseases associated with their dysfunction are reviewed.
Abstract: The AAA+ (ATPases associated with various cellular activities) family is a large and functionally diverse group of enzymes that are able to induce conformational changes in a wide range of substrate proteins. The family's defining feature is a structurally conserved ATPase domain that assembles into oligomeric rings and undergoes conformational changes during cycles of nucleotide binding and hydrolysis. Here, we review the structural organization of AAA+ proteins, the conformational changes they undergo, the range of different reactions they catalyse, and the diseases associated with their dysfunction.
1,137 citations
Cites background from "Sculpting the Proteome with AAA+ Pr..."
...This positions the tagged substrate near the ClpX por...
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TL;DR: A bacterial organelle that has specifically evolved to deliver bacterial proteins into eukaryotic cells is encoded by a large number of bacterial species that are symbiotic or pathogenic for humans, other animals including insects or nematodes, and plants.
Abstract: Bacteria that have sustained long-standing close associations with eukaryotic hosts have evolved specific adaptations to survive and replicate in this environment. Perhaps one of the most remarkable of those adaptations is the type III secretion system (T3SS)--a bacterial organelle that has specifically evolved to deliver bacterial proteins into eukaryotic cells. Although originally identified in a handful of pathogenic bacteria, T3SSs are encoded by a large number of bacterial species that are symbiotic or pathogenic for humans, other animals including insects or nematodes, and plants. The study of these systems is leading to unique insights into not only organelle assembly and protein secretion but also mechanisms of symbiosis and pathogenesis.
1,031 citations
TL;DR: This introductory article will focus on discussion of the essential roles of proteases in cell behavior and survival and death of all organisms, and the large collection of findings demonstrating their relevance in the control of multiple biological processes in all living organisms.
780 citations
References
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TL;DR: This review discusses recent information on functions and mechanisms of the ubiquitin system and focuses on what the authors know, and would like to know, about the mode of action of ubi...
Abstract: The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.
7,888 citations
"Sculpting the Proteome with AAA+ Pr..." refers background in this paper
...Protein substrates of the 26S proteasome of eukaryotic cells are marked for destruction by covalent attachment of polyubiquitin chains, via the sequential actions of the E1, E2, and E3 enzymes (Hershko and Ciechanover, 1998)....
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TL;DR: Two β-type subunits are processed to an intermediate form, indicating that an additional nonspecific endopeptidase activity may exist which is important for peptide hydrolysis and for the generation of ligands for class I molecules of the major histocompatibility complex.
Abstract: The crystal structure of the 20S proteasome from the yeast Saccharomyces cerevisiae shows that its 28 protein subunits are arranged as an (α1...α7, β1...β7)2 complex in four stacked rings and occupy unique locations. The interior of the particle, which harbours the active sites, is only accessible by some very narrow side entrances. The β-type subunits are synthesized as proproteins before being proteolytically processed for assembly into the particle. The proforms of three of the seven different β-type subunits, (β1/PRE3, β2/PUP1 and β5/PRE2, are cleaved between the threonine at position 1 and the last glycine of the pro-sequence, with release of the active-site residue Thr 1. These three β-type subunits have inhibitor-binding sites, indicating that PRE2 has a chymotrypsin-like and a trypsin-like activity and that PRE3 has peptidylglutamyl peptide hydrolytic specificity. Other β-type subunits are processed to an intermediate form, indicating that an additional nonspecific endopeptidase activity may exist which is important for peptide hydrolysis and for the generation of ligands for class I molecules of the major histocompatibility complex.
2,235 citations
"Sculpting the Proteome with AAA+ Pr..." refers background in this paper
...The 20S proteasome peptidases of archaea and eukaryotes are constructed in a similar fashion to the bacterial compartmental peptidases (Löwe et al., 1995; Groll et al., 1997)....
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...…peptidases of archaea and and the rotary F1F0 ATP synthase. eukaryotes are constructed in a similar fashion to the This review will focus on the mechanism and regula- bacterial compartmental peptidases (Löwe et al., 1995; tion of ATP-dependent protein degradation, unfolding, Groll et al., 1997)....
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TL;DR: Whole-genome analysis indicates that this class of proteins is ancient and has undergone considerable functional divergence prior to the emergence of the major divisions of life.
Abstract: Using a combination of computer methods for iterative database searches and multiple sequence alignment, we show that protein sequences related to the AAA family of ATPases are far more prevalent than reported previously. Among these are regulatory components of Lon and Clp proteases, proteins involved in DNA replication, recombination, and restriction (including subunits of the origin recognition complex, replication factor C proteins, MCM DNA-licensing factors and the bacterial DnaA, RuvB, and McrB proteins), prokaryotic NtrC-related transcription regulators, the Bacillus sporulation protein SpoVJ, Mg2+, and Co2+ chelatases, the Halobacterium GvpN gas vesicle synthesis protein, dynein motor proteins, TorsinA, and Rubisco activase. Alignment of these sequences, in light of the structures of the clamp loader delta' subunit of Escherichia coli DNA polymerase III and the hexamerization component of N-ethylmaleimide-sensitive fusion protein, provides structural and mechanistic insights into these proteins, collectively designated the AAA+ class. Whole-genome analysis indicates that this class is ancient and has undergone considerable functional divergence prior to the emergence of the major divisions of life. These proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes. The hexameric architecture often associated with this class can provide a hole through which DNA or RNA can be thread; this may be important for assembly or remodeling of DNA-protein complexes.
1,830 citations
"Sculpting the Proteome with AAA+ Pr..." refers background in this paper
...In fact, the intracellular levels of many ClpXPmotifs are found in all AAA ATPases (Schirmer et al., 1996; Neuwald et al., 1999). substrates change in response to oxygen levels, starvation, DNA damage, heat and cold shock, etc. (Flynn et al., 2003)....
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...Likewise, some activators of the proteasome increase the diameter of the portal to 1996; Neuwald et al., 1999)....
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...The bacterial AAA+ enzymes that function in proteolysis and disassembly are ring hexamers, containing one or two ATPase modules per polypeptide (Schirmer et al., 1996; Neuwald et al., 1999)....
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TL;DR: The three-dimensional structure of the proteasome from the archaebacterium Thermoplasma acidophilum has been elucidated by x-ray crystallographic analysis by means of isomorphous replacement and cyclic averaging.
Abstract: The three-dimensional structure of the proteasome from the archaebacterium Thermoplasma acidophilum has been elucidated by x-ray crystallographic analysis by means of isomorphous replacement and cyclic averaging. The atomic model was built and refined to a crystallographic R factor of 22.1 percent. The 673-kilodalton protease complex consists of 14 copies of two different subunits, alpha and beta, forming a barrel-shaped structure of four stacked rings. The two inner rings consist of seven beta subunits each, and the two outer rings consist of seven alpha subunits each. A narrow channel controls access to the three inner compartments. The alpha 7 beta 7 beta 7 alpha 7 subunit assembly has 72-point group symmetry. The structures of the alpha and beta subunits are similar, consisting of a core of two antiparallel beta sheets that is flanked by alpha helices on both sides. The binding of a peptide aldehyde inhibitor marks the active site in the central cavity at the amino termini of the beta subunits and suggests a novel proteolytic mechanism.
1,532 citations