|Gene:||ftsH||Accession Numbers: EG11506 (EcoCyc), b3178, ECK3167|
Synonyms: std, hflB, mrsC, tolZ
Component of: HflB, integral membrane ATP-dependent zinc metallopeptidase (extended summary available)
FtsH is a membrane-bound, ATP-dependent metalloprotease which has been shown to be involved in the degradation of some aberrant membrane and cytoplasmic proteins [Akiyama00, Akiyama96, Akiyama98, Akiyama96, Kihara95]. FtsH-mediated proteolysis has been shown to be directly related to the proton motive force (pmf) across the membrane [Akiyama03]. Topology mapping indicates that FtsH has two transmembrane segments near the N-terminus and a large cytoplasmic domain which comprises two subdomains: an ATPase domain and a zinc metalloprotease motif-containing protease domain [Tomoyasu93].
Deletion mutation studies have shown that FtsH may also play a role in the proper assembly of proteins into and through the inner membrane by assuring effective stop-transfer of some transmembrane proteins [Akiyama94a]. Protein purification and cross-linking studies indicate that FtsH is physically and functionally connected to YidC and that this complex may be involved in quality control of inner membrane proteins (IMPs) during biogenesis [vanBloois08].
Locations: inner membrane
|Map Position: [3,323,023 <- 3,324,957] (71.62 centisomes)||Length: 1935 bp / 644 aa|
Molecular Weight of Polypeptide: 70.708 kD (from nucleotide sequence)
Unification Links: ASAP:ABE-0010444 , CGSC:735 , DIP:DIP-35828N , EchoBASE:EB1469 , EcoGene:EG11506 , EcoliWiki:b3178 , Mint:MINT-1226643 , ModBase:P0AAI3 , OU-Microarray:b3178 , PortEco:ftsH , PR:PRO_000022717 , Pride:P0AAI3 , Protein Model Portal:P0AAI3 , RefSeq:NP_417645 , RegulonDB:EG11506 , SMR:P0AAI3 , String:511145.b3178 , Swiss-Model:P0AAI3 , UniProt:P0AAI3
Relationship Links: InterPro:IN-FAMILY:IPR000642 , InterPro:IN-FAMILY:IPR003593 , InterPro:IN-FAMILY:IPR003959 , InterPro:IN-FAMILY:IPR003960 , InterPro:IN-FAMILY:IPR005936 , InterPro:IN-FAMILY:IPR011546 , InterPro:IN-FAMILY:IPR027417 , PDB:Structure:1LV7 , Pfam:IN-FAMILY:PF00004 , Pfam:IN-FAMILY:PF01434 , Pfam:IN-FAMILY:PF06480 , Prosite:IN-FAMILY:PS00674 , Smart:IN-FAMILY:SM00382
In Paralogous Gene Group: 134 (5 members)
|Biological Process:||GO:0006200 - ATP catabolic process
GO:0006508 - proteolysis [UniProtGOA11, GOA01, Tomoyasu95]
GO:0030163 - protein catabolic process [GOA06]
|Molecular Function:||GO:0008270 - zinc ion binding
[GOA06, GOA01, Tomoyasu95]
GO:0016887 - ATPase activity [GOA06, Tomoyasu95]
GO:0030145 - manganese ion binding [Tomoyasu95]
GO:0043273 - CTPase activity [Tomoyasu95]
GO:0000166 - nucleotide binding [UniProtGOA11]
GO:0004222 - metalloendopeptidase activity [GOA01]
GO:0005524 - ATP binding [UniProtGOA11, GOA06, GOA01]
GO:0008233 - peptidase activity [UniProtGOA11, GOA06]
GO:0008237 - metallopeptidase activity [UniProtGOA11]
GO:0016787 - hydrolase activity [UniProtGOA11]
GO:0046872 - metal ion binding [UniProtGOA11]
|Cellular Component:||GO:0016021 - integral component of membrane
[UniProtGOA11, GOA01, Tomoyasu93]
GO:0005886 - plasma membrane [UniProtGOA11a, UniProtGOA11, Tomoyasu93]
GO:0016020 - membrane [UniProtGOA11, GOA01]
|MultiFun Terms:||cell processes → cell division|
|cell structure → membrane|
|extrachromosomal → plasmid related|
|information transfer → protein related → turnover, degradation|
|information transfer → RNA related → Transcription related|
|metabolism → degradation of macromolecules → proteins/peptides/glycopeptides|
|Growth Medium||Growth?||T (°C)||O2||pH||Osm/L||Growth Observations|
|LB enriched||Yes||37||Aerobic||6.95||Yes [Gerdes03, Comment 1]|
|LB Lennox||No||37||Aerobic||7||No [Baba06, Comment 2]|
Subunit composition of
HflB, integral membrane ATP-dependent zinc metallopeptidase = [(HflK)(HflC)]6[FtsH]6
HflK-HflC complex; regulator of FtsH protease = (HflK)(HflC) (extended summary available)
regulator of FtsH protease = HflK (summary available)
regulator of FtsH protease = HflC (summary available)
ATP-dependent zinc metalloprotease FtsH = FtsH (extended summary available)
FtsH is a zinc-dependent metalloendoprotease required for survival [Jayasekera00]. Cells lacking functional FtsH fail to septate, instead forming multinucleate filaments [Santos75]. FtsH degrades a number of cellular proteins, including the membrane protein YccA and orphaned complex components such as SecY in the absence of SecE and unaccompanied ATPase F0 [Kihara98, Kihara95, Akiyama96a]. FtsH degrades SecY and to a lesser extent SecE in LamB-LacZ fusion strains with a 'jammed' Sec translocator [vanStelten09]. FtsH degrades the heat shock promoter protein sigma32 [Herman95]. FtsH also controls the abundance of a number of phage proteins, modulating levels of lambda cIII, cleaving cII into peptides of 13-20 residues and degrading Xis, which is required for excision of lambda phage from the chromosome [Herman97, Shotland00, Leffers98]. In addition to the roles described above, FtsH can also break down proteins tagged with the SsrA degradation peptide [Herman98, Herman03a].
FtsH is a multiprotein complex comprising a hexamer of FtsH monomers and a hexamer of HflKC pairs [Karata01, Saikawa, Bruckner03]. Though the FtsH monomer can bind both ATP and denatured protein, only the hexamer is capable of proteolysis, and the FtsH membrane domain is required for oligomerization and degradation of membrane protein substrates, even with solubilized membrane proteins [Akiyama95, Makino99, Akiyama01, Akiyama00]. The periplasmic portion of the FtsH monomer is required for degradation of cII, as well as for effective interaction between FtsH and HflKC [Akiyama98]. As with many AAA proteases, FtsH has a proteolytic component, the FtsH monomer and a regulatory component, HflKC, which modulates its protease activity [Dougan02, Kihara96, Kihara97].
The crystal structure of the ATPase module has been solved and is similar to other AAA domains [Krzywda02, Krzywda02a]. Three leucines in a coiled-coil motif at the carboxy-terminus of the FtsH subunit are required for proteolytic and substrate binding activities though they are not needed for ATPase function [Shotland00a]. Phenylalanine-228 and glycine-230, predicted to be in the central pore of the FtsH hexamer, are required for ATPase function and proteolysis of casein, though mutants lacking Phenylalanine-228 were still able to degrade sigma32 [YamadaInagawa03]. FtsH has a zinc-binding motif and requires zinc for its proteolytic function [Tomoyasu95]. Glutamate-479 is one of the residues coordinating this zinc cofactor [Saikawa02].
FtsH function is ATP dependent, with ATP binding to two sites in the carboxy-terminal ATPase module of FtsH and inducing a conformational change [Akiyama94b, Akiyama96, Akiyama98a]. Mutations in the SRH (Second Region of Homology) portion of the FtsH subunit disrupt the protein's ATPase and protease activities, but still allow this conformational change, suggesting that binding of ATP alone is insufficient for activation of the protease [Karata99]. FtsH takes two minutes to degrade sigma32 and uses 140 ATP molecules to do so [Okuno04].
FtsH degradation of cII in vitro does not require any chaperones and proceeds ten times faster than degradation of sigma32 [Shotland97]. FtsH cleaves cII into peptides of 13-20 peptides without much cut-site specificity [Shotland00]. The carboxy-terminal end of cII is required for FtsH degradation, and can also prompt degradation of other proteins if if is appended to them. Degradation of cII is inhibited by cIII and requires HflD [Kobiler02, Kihara01a].
FtsH is able to dislocate membrane proteins from the membrane and is able to degrade from both the amino- and carboxy-terminal ends of its substrates [Kihara99, Okuno04]. Degradation of YccA depends on its amino-terminal tail being twenty residues long or longer, though there is no sequence specificity involved and adding twenty-residue tails to SecE and Y sensitized them to FtsH-mediated degradation [Chiba00]. Proteolysis from the amino-terminus requires only ten residues [Chiba02]. FtsH proteolyzes Arc repressor when it is tagged with the SsrA degradation tag, breaking the protein down from the tagged end. Generally, FtsH is most effective at degrading thermodynamically unstable proteins [Herman03a].
FtsH-mediated degradation of sigma32 has been shown to either require or not require its carboxy-terminus and to depend on proper sequence in the middle of the protein [Blaszczak99, Tomoyasu01, Bertani01]. Sigma32 is broken down into ten peptide products less than 3 kDa in size [Bruckner03].
FtsH degradation in membrane vesicles requires only FtsH, substrate and ATP [Akiyama03]. In vivo, degradation slows when the proton-motive force is diminished and is stimulated by enhancement of the proton-motive force [Akiyama02].
FtsH cleaves the carboxy-terminus of the FtsH subunit in an ATP-dependent manner. The cut, between methionine-640 and serine-641, removes five residues from the end of the protein and appears not to affect protein function [Akiyama99a].
Loss of FtsH or its ATPase activity results in "stop-transfer defects," or mislocalization of protein segments that are normally anchored in the membranes or transported out of the cell [Akiyama94a]. This may relate to the role of FtsH in maintenance of proper membrane structures and LPS production, possibly based on degradation of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC/EnvA) [Ogura99]. Similarly, the effect of FtsH on membranes may explain the requirement for FtsH in proper plasmid partitioning [Inagawa01]. FtsH is required for sensitivity to colicin [Holland76, Matsuzawa84, Qu96].
Locations: inner membrane
|Cellular Component:||GO:0005886 - plasma membrane [Tomoyasu93]|
Enzymatic reaction of: ATP-dependent zinc metalloendoprotease (HflB, integral membrane ATP-dependent zinc metallopeptidase)
EC Number: 3.4.24.-
The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.
The reaction is physiologically favored in the direction shown.
|Transmembrane-Region||5 -> 25|
|Transmembrane-Region||99 -> 119|
|Nucleotide-Phosphate-Binding-Region||192 -> 199|
3/19/1998 (pkarp) Merged genes G528/b3178 and EG11506/hflB
10/20/97 Gene b3178 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG11506; confirmed by SwissProt match.
Akiyama02: Akiyama Y (2002). "Proton-motive force stimulates the proteolytic activity of FtsH, a membrane-bound ATP-dependent protease in Escherichia coli." Proc Natl Acad Sci U S A 99(12);8066-71. PMID: 12034886
Akiyama94a: Akiyama Y, Ogura T, Ito K (1994). "Involvement of FtsH in protein assembly into and through the membrane. I. Mutations that reduce retention efficiency of a cytoplasmic reporter." J Biol Chem 269(7);5218-24. PMID: 8106504
Akiyama94b: Akiyama Y, Shirai Y, Ito K (1994). "Involvement of FtsH in protein assembly into and through the membrane. II. Dominant mutations affecting FtsH functions." J Biol Chem 269(7);5225-9. PMID: 8106505
Akiyama96: Akiyama Y, Kihara A, Tokuda H, Ito K (1996). "FtsH (HflB) is an ATP-dependent protease selectively acting on SecY and some other membrane proteins." J Biol Chem 271(49);31196-201. PMID: 8940120
Akiyama98: Akiyama Y, Kihara A, Mori H, Ogura T, Ito K (1998). "Roles of the periplasmic domain of Escherichia coli FtsH (HflB) in protein interactions and activity modulation." J Biol Chem 273(35);22326-33. PMID: 9712851
Baba06: Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H (2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection." Mol Syst Biol 2;2006.0008. PMID: 16738554
Bertani01: Bertani D, Oppenheim AB, Narberhaus F (2001). "An internal region of the RpoH heat shock transcription factor is critical for rapid degradation by the FtsH protease." FEBS Lett 493(1);17-20. PMID: 11277997
Blaszczak99: Blaszczak A, Georgopoulos C, Liberek K (1999). "On the mechanism of FtsH-dependent degradation of the sigma 32 transcriptional regulator of Escherichia coli and the role of the Dnak chaperone machine." Mol Microbiol 31(1);157-66. PMID: 9987118
Gerdes03: Gerdes SY, Scholle MD, Campbell JW, Balazsi G, Ravasz E, Daugherty MD, Somera AL, Kyrpides NC, Anderson I, Gelfand MS, Bhattacharya A, Kapatral V, D'Souza M, Baev MV, Grechkin Y, Mseeh F, Fonstein MY, Overbeek R, Barabasi AL, Oltvai ZN, Osterman AL (2003). "Experimental determination and system level analysis of essential genes in Escherichia coli MG1655." J Bacteriol 185(19);5673-84. PMID: 13129938
Granger98: Granger LL, O'Hara EB, Wang RF, Meffen FV, Armstrong K, Yancey SD, Babitzke P, Kushner SR (1998). "The Escherichia coli mrsC gene is required for cell growth and mRNA decay." J Bacteriol 180(7);1920-8. PMID: 9537393
Herman03a: Herman C, Prakash S, Lu CZ, Matouschek A, Gross CA (2003). "Lack of a robust unfoldase activity confers a unique level of substrate specificity to the universal AAA protease FtsH." Mol Cell 11(3);659-69. PMID: 12667449
Herman95: Herman C, Thevenet D, D'Ari R, Bouloc P (1995). "Degradation of sigma 32, the heat shock regulator in Escherichia coli, is governed by HflB." Proc Natl Acad Sci U S A 1995;92(8);3516-20. PMID: 7724592
Herman98: Herman C, Thevenet D, Bouloc P, Walker GC, D'Ari R (1998). "Degradation of carboxy-terminal-tagged cytoplasmic proteins by the Escherichia coli protease HflB (FtsH)." Genes Dev 12(9);1348-55. PMID: 9573051
Karata01: Karata K, Verma CS, Wilkinson AJ, Ogura T (2001). "Probing the mechanism of ATP hydrolysis and substrate translocation in the AAA protease FtsH by modelling and mutagenesis." Mol Microbiol 39(4);890-903. PMID: 11251810
Karata99: Karata K, Inagawa T, Wilkinson AJ, Tatsuta T, Ogura T (1999). "Dissecting the role of a conserved motif (the second region of homology) in the AAA family of ATPases. Site-directed mutagenesis of the ATP-dependent protease FtsH." J Biol Chem 274(37);26225-32. PMID: 10473576
Kihara01a: Kihara A, Akiyama Y, Ito K (2001). "Revisiting the lysogenization control of bacteriophage lambda. Identification and characterization of a new host component, HflD." J Biol Chem 276(17);13695-700. PMID: 11278968
Kihara95: Kihara A, Akiyama Y, Ito K (1995). "FtsH is required for proteolytic elimination of uncomplexed forms of SecY, an essential protein translocase subunit." Proc Natl Acad Sci U S A 92(10);4532-6. PMID: 7753838
Kihara96: Kihara A, Akiyama Y, Ito K (1996). "A protease complex in the Escherichia coli plasma membrane: HflKC (HflA) forms a complex with FtsH (HflB), regulating its proteolytic activity against SecY." EMBO J 15(22);6122-31. PMID: 8947034
Kihara97: Kihara A, Akiyama Y, Ito K (1997). "Host regulation of lysogenic decision in bacteriophage lambda: transmembrane modulation of FtsH (HflB), the cII degrading protease, by HflKC (HflA)." Proc Natl Acad Sci U S A 94(11);5544-9. PMID: 9159109
Kihara98: Kihara A, Akiyama Y, Ito K (1998). "Different pathways for protein degradation by the FtsH/HflKC membrane-embedded protease complex: an implication from the interference by a mutant form of a new substrate protein, YccA." J Mol Biol 279(1);175-88. PMID: 9636708
Kobiler02: Kobiler O, Koby S, Teff D, Court D, Oppenheim AB (2002). "The phage lambda CII transcriptional activator carries a C-terminal domain signaling for rapid proteolysis." Proc Natl Acad Sci U S A 99(23);14964-9. PMID: 12397182
Krzywda02: Krzywda S, Brzozowski AM, Verma C, Karata K, Ogura T, Wilkinson AJ (2002). "The crystal structure of the AAA domain of the ATP-dependent protease FtsH of Escherichia coli at 1.5 A resolution." Structure (Camb) 10(8);1073-83. PMID: 12176385
Krzywda02a: Krzywda S, Brzozowski AM, Karata K, Ogura T, Wilkinson AJ (2002). "Crystallization of the AAA domain of the ATP-dependent protease FtsH of Escherichia coli." Acta Crystallogr D Biol Crystallogr 58(Pt 6 Pt 2);1066-7. PMID: 12037319
Makino99: Makino S, Makino T, Abe K, Hashimoto J, Tatsuta T, Kitagawa M, Mori H, Ogura T, Fujii T, Fushinobu S, Wakagi T, Matsuzawa H, Makinoa T (1999). "Second transmembrane segment of FtsH plays a role in its proteolytic activity and homo-oligomerization." FEBS Lett 460(3);554-8. PMID: 10556534
Matsuzawa84: Matsuzawa H, Ushiyama S, Koyama Y, Ohta T (1984). "Escherichia coli K-12 tolZ mutants tolerant to colicins E2, E3, D, Ia, and Ib: defect in generation of the electrochemical proton gradient." J Bacteriol 160(2);733-9. PMID: 6389496
Ogura99: Ogura T, Inoue K, Tatsuta T, Suzaki T, Karata K, Young K, Su LH, Fierke CA, Jackman JE, Raetz CR, Coleman J, Tomoyasu T, Matsuzawa H (1999). "Balanced biosynthesis of major membrane components through regulated degradation of the committed enzyme of lipid A biosynthesis by the AAA protease FtsH (HflB) in Escherichia coli." Mol Microbiol 31(3);833-44. PMID: 10048027
Okuno04: Okuno T, Yamada-Inagawa T, Karata K, Yamanaka K, Ogura T (2004). "Spectrometric analysis of degradation of a physiological substrate sigma32 by Escherichia coli AAA protease FtsH." J Struct Biol 146(1-2);148-54. PMID: 15037246
Qu96: Qu JN, Makino SI, Adachi H, Koyama Y, Akiyama Y, Ito K, Tomoyasu T, Ogura T, Matsuzawa H (1996). "The tolZ gene of Escherichia coli is identified as the ftsH gene." J Bacteriol 178(12);3457-61. PMID: 8655541
Shotland00: Shotland Y, Shifrin A, Ziv T, Teff D, Koby S, Kobiler O, Oppenheim AB (2000). "Proteolysis of bacteriophage lambda CII by Escherichia coli FtsH (HflB)." J Bacteriol 182(11);3111-6. PMID: 10809689
Shotland00a: Shotland Y, Teff D, Koby S, Kobiler O, Oppenheim AB (2000). "Characterization of a conserved alpha-helical, coiled-coil motif at the C-terminal domain of the ATP-dependent FtsH (HflB) protease of Escherichia coli." J Mol Biol 299(4);953-64. PMID: 10843850
Shotland97: Shotland Y, Koby S, Teff D, Mansur N, Oren DA, Tatematsu K, Tomoyasu T, Kessel M, Bukau B, Ogura T, Oppenheim AB (1997). "Proteolysis of the phage lambda CII regulatory protein by FtsH (HflB) of Escherichia coli." Mol Microbiol 24(6);1303-10. PMID: 9218777
Tomoyasu93: Tomoyasu T, Yamanaka K, Murata K, Suzaki T, Bouloc P, Kato A, Niki H, Hiraga S, Ogura T (1993). "Topology and subcellular localization of FtsH protein in Escherichia coli." J Bacteriol 175(5);1352-7. PMID: 8444797
Tomoyasu93a: Tomoyasu T, Yuki T, Morimura S, Mori H, Yamanaka K, Niki H, Hiraga S, Ogura T (1993). "The Escherichia coli FtsH protein is a prokaryotic member of a protein family of putative ATPases involved in membrane functions, cell cycle control, and gene expression." J Bacteriol 1993;175(5);1344-51. PMID: 8444796
Tomoyasu95: Tomoyasu T, Gamer J, Bukau B, Kanemori M, Mori H, Rutman AJ, Oppenheim AB, Yura T, Yamanaka K, Niki H (1995). "Escherichia coli FtsH is a membrane-bound, ATP-dependent protease which degrades the heat-shock transcription factor sigma 32." EMBO J 14(11);2551-60. PMID: 7781608
vanBloois08: van Bloois E, Dekker HL, Froderberg L, Houben EN, Urbanus ML, de Koster CG, de Gier JW, Luirink J (2008). "Detection of cross-links between FtsH, YidC, HflK/C suggests a linked role for these proteins in quality control upon insertion of bacterial inner membrane proteins." FEBS Lett 582(10);1419-24. PMID: 18387365
vanStelten09: van Stelten J, Silva F, Belin D, Silhavy TJ (2009). "Effects of antibiotics and a proto-oncogene homolog on destruction of protein translocator SecY." Science 325(5941);753-6. PMID: 19661432
Wang98i: Wang RF, O'Hara EB, Aldea M, Bargmann CI, Gromley H, Kushner SR (1998). "Escherichia coli mrsC is an allele of hflB, encoding a membrane-associated ATPase and protease that is required for mRNA decay." J Bacteriol 180(7);1929-38. PMID: 9537394
YamadaInagawa03: Yamada-Inagawa T, Okuno T, Karata K, Yamanaka K, Ogura T (2003). "Conserved pore residues in the AAA protease FtsH are important for proteolysis and its coupling to ATP hydrolysis." J Biol Chem 278(50);50182-7. PMID: 14514680
Nonaka06: Nonaka G, Blankschien M, Herman C, Gross CA, Rhodius VA (2006). "Regulon and promoter analysis of the E. coli heat-shock factor, sigma32, reveals a multifaceted cellular response to heat stress." Genes Dev 20(13);1776-89. PMID: 16818608
Partridge09: Partridge JD, Bodenmiller DM, Humphrys MS, Spiro S (2009). "NsrR targets in the Escherichia coli genome: new insights into DNA sequence requirements for binding and a role for NsrR in the regulation of motility." Mol Microbiol 73(4);680-94. PMID: 19656291
Wade06: Wade JT, Roa DC, Grainger DC, Hurd D, Busby SJ, Struhl K, Nudler E (2006). "Extensive functional overlap between sigma factors in Escherichia coli." Nat Struct Mol Biol 13(9);806-14. PMID: 16892065
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