FtsH Recognizes Proteins with Unfolded Structure and Hydrolyzes the Carboxyl Side of Hydrophobic Residues

Asahara, Yuko; Atsuta, Kyoko; Motohashi, Ken; Taguchi, Hideki; Yohda, Masafumi; Yoshida, Masasuke

doi:10.1093/oxfordjournals.jbchem.a022689

Cited by 36 publications

(36 citation statements)

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“…Nevertheless, it will be interesting to test whether substrates additionally stimulate the activity of their cognate Torsin ATPases. α-Casein, a constitutively misfolded protein that stimulates a host of AAA+ ATPases implicated in protein quality control, including other membrane-associated representatives (28,29), did not stimulate the activity of TorA (Fig. S4).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Torsin ATPases by LAP1 and LULL1

Zhao

Brown

Chase

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

134

237

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TorsinA is a membrane-associated AAA+ (ATPases associated with a variety of cellular activities) ATPase implicated in primary dystonia, an autosomal-dominant movement disorder. We reconstituted TorsinA and its cofactors in vitro and show that TorsinA does not display ATPase activity in isolation; ATP hydrolysis is induced upon association with LAP1 and LULL1, type II transmembrane proteins residing in the nuclear envelope and endoplasmic reticulum. This interaction requires TorsinA to be in the ATP-bound state, and can be attributed to the luminal domains of LAP1 and LULL1. This ATPase activator function controls the activities of other members of the Torsin family in distinct fashion, leading to an acceleration of the hydrolysis step by up to two orders of magnitude. The dystonia-causing mutant of TorsinA is defective in this activation mechanism, suggesting a loss-of-function mechanism for this congenital disorder.DYT1 dystonia | LINC complex | nuclear egress

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Section: Discussionmentioning

confidence: 99%

Regulation of Torsin ATPases by LAP1 and LULL1

Zhao

Brown

Chase

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

134

237

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“…FtsH may be a processive endopeptidase, since its degradation products are not amino acid monomers but oligopeptides of several residues (7,39). Thus, within the putative catalytic chamber of FtsH, the substrate polypeptide could have some degree of flexibility such that the peptide bond to be hydrolyzed is always presented to the active site with a fixed directionality.…”

Section: Discussionmentioning

confidence: 99%

Membrane Protein Degradation by FtsH Can Be Initiated from Either End

2002

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FtsH, a membrane-bound metalloprotease, with cytoplasmic metalloprotease and AAA ATPase domains, degrades both soluble and integral membrane proteins in Escherichia coli. In this paper we investigated how membrane-embedded substrates are recognized by this enzyme. We showed previously that FtsH can initiate processive proteolysis at an N-terminal cytosolic tail of a membrane protein, by recognizing its length (more than 20 amino acid residues) but not exact sequence. Subsequent proteolysis should involve dislocation of the substrates into the cytosol. We now show that this enzyme can also initiate proteolysis at a C-terminal cytosolic tail and that the initiation efficiency depends on the length of the tail. This mode of degradation also appeared to be processive, which can be aborted by a tightly folded periplasmic domain. These results indicate that FtsH can exhibit processivity against membrane-embedded substrates in either the N-to-C or C-to-N direction. Our results also suggest that some membrane proteins receive bidirectional degradation simultaneously. These results raise intriguing questions about the molecular directionality of the dislocation and proteolysis catalyzed by FtsH.Energy-dependent proteolysis plays important roles in controlling and maintaining cellular functions. Whereas the 26S proteasome is a key player of these events in eukaryotic cells, HslUV, ClpAP, ClpXP, Lon, and FtsH and their homologs are known as ATP-dependent proteases in bacteria (13,23,38) as well as in the mitochondria and the chloroplasts (1, 23). The ATPase domains or subunits of these proteases belong to the AAAϩ ATPase family (29,34,38). Many of them are known to form ring-like assemblies of subunits (31, 43). The proteolytic active sites of these enzymes are thought to be located in the interior cavity of the assemblies; experimentally this has been shown for the proteasome, HslUV, ClpAP, and ClpXP (8,15,26,44). For the substrate peptide bond to be hydrolyzed, it must be presented to the catalytic center within the cavity. This implies that the substrate protein itself must be unfolded and translocated into the catalytic chamber (18,33,35). Presumably, these proteases utilize their ATPase functions to facilitate unfolding and translocation of substrate proteins.A characteristic feature of the energy-dependent proteolytic reactions is that they occur in processive manners (24). Once the enzyme initiates the reaction, it continues to work along the polypeptide chain to hydrolyze the substrate successively. Crucial questions here include (i) how the enzyme recognizes the initiation site on the substrate, (ii) how it initiates unfolding or translocation of the substrate, and (iii) how it continues the reaction along the polypeptide chain, expelling the product small peptides from the catalytic chamber. Studies on the Clp proteases demonstrated that these enzymes can recognize either the N-or C-terminal end of substrate polypeptides for the initiation of unfolding or proteolysis (12,14,17).Among the ATP-dependent proteases i...

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“…The elution patterns for all time points shown are identical, only the amount of the individual degradation products increased over the reaction time. This showed that TaLon degraded substrates in a processive manner, which is a characteristic feature of ATP-dependent proteases, e.g., E. coli ClpP protease, archaeal and mammalian 20S proteasomes, mammalian 26S proteasomes and E. coli and T. thermophilus FtsH proteases [26][27][28][29][30].…”

Section: Degradation Of Fitc Caseinmentioning

confidence: 99%

Mutational analysis of conserved AAA⁺ residues in the archaeal Lon protease from Thermoplasma acidophilum

Besche

Tamura

et al. 2004

FEBS Letters

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The Lon protease from the archaeon Thermoplasma acidophilum (TaLon) is composed of an N-terminal ATPase associated with various cellular activities (AAA þ ) domain and a C-terminal Lon protease domain. Although related in sequence to the soluble Lon proteases, TaLon was shown to be membranebound in its native host and also when expressed in Escherichia coli. Recombinant TaLon was purified as a functional highmolecular weight complex displaying ATPase and proteolytic activity. Mutagenesis of conserved AAA þ residues revealed that the Walker A and B motifs, and the sensor 1 and sensor 2 0 residues were essential for the ATPase activity, while the sensor 2 and the arginine finger were involved in activation of the protease domain.

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FtsH Recognizes Proteins with Unfolded Structure and Hydrolyzes the Carboxyl Side of Hydrophobic Residues

Cited by 36 publications

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Regulation of Torsin ATPases by LAP1 and LULL1

Regulation of Torsin ATPases by LAP1 and LULL1

Membrane Protein Degradation by FtsH Can Be Initiated from Either End

Mutational analysis of conserved AAA⁺ residues in the archaeal Lon protease from Thermoplasma acidophilum

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FtsH Recognizes Proteins with Unfolded Structure and Hydrolyzes the Carboxyl Side of Hydrophobic Residues

Cited by 36 publications

References 0 publications

Regulation of Torsin ATPases by LAP1 and LULL1

Regulation of Torsin ATPases by LAP1 and LULL1

Membrane Protein Degradation by FtsH Can Be Initiated from Either End

Mutational analysis of conserved AAA+ residues in the archaeal Lon protease from Thermoplasma acidophilum

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Mutational analysis of conserved AAA⁺ residues in the archaeal Lon protease from Thermoplasma acidophilum