{{Short description|Bacterial protein that is related to actin}} {{Infobox nonhuman protein | Name = FtsA | image = Xenorhabdus poinarii FtsA.png | caption = Ribbon diagram of FtsA, with ADP bound to active site (multi-color sticks) and divalent magnesium cation (green sphere) highlighted. | Organism = Xenorhabdus poinarii | Symbol = FtsA | AltSymbols = Cell division protein FtsA | PDB = 7Q6G | RefSeqProtein = | UniProt = A0A068QZX9 }} {{Infobox protein family|Name=FtsA|Symbol=FtsA|InterPro=IPR020823}} {{Infobox protein family|Name=SHS2 "1C" domain inserted in FtsA|Symbol=SHS2_FtsA|InterPro=IPR003494|Pfam=PF02491|SMART=SM00842}}
'''FtsA''' is a bacterial protein that is related to actin by overall structural similarity and in its ATP binding pocket.<ref name="pmid11032797">{{cite journal | vauthors = van den Ent F, Löwe J | title = Crystal structure of the cell division protein FtsA from Thermotoga maritima | journal = The EMBO Journal | volume = 19 | issue = 20 | pages = 5300–7 | date = Oct 2000 | pmid = 11032797 | doi = 10.1093/emboj/19.20.5300 | pmc=313995}}</ref><ref name="pmid25788699">{{cite journal | vauthors = Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC | title = The evolution of compositionally and functionally distinct actin filaments | journal = Journal of Cell Science | volume = 128 | issue = 11 | pages = 2009–19 | date = Jun 2015 | pmid = 25788699 | doi = 10.1242/jcs.165563 | doi-access = free }}</ref><ref name="pnas_actin">{{cite journal | vauthors = Ghoshdastider U, Jiang S, Popp D, Robinson RC | title = In search of the primordial actin filament | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 30 | pages = 9150–1 | date = Jul 2015 | pmid = 26178194 | doi = 10.1073/pnas.1511568112 | pmc=4522752| doi-access = free }}</ref> It is involved in bacterial cell division, where it serves to tether the cytokinetic ring formed by FtsZ to the cytoplasmic membrane prior to division.<ref name=":0">{{Cite journal |last1=Nierhaus |first1=Tim |last2=McLaughlin |first2=Stephen H. |last3=Bürmann |first3=Frank |last4=Kureisaite-Ciziene |first4=Danguole |last5=Maslen |first5=Sarah L. |last6=Skehel |first6=J. Mark |last7=Yu |first7=Conny W. H. |last8=Freund |first8=Stefan M. V. |last9=Funke |first9=Louise F. H. |last10=Chin |first10=Jason W. |last11=Löwe |first11=Jan |date=October 2022 |title=Bacterial divisome protein FtsA forms curved antiparallel double filaments when binding to FtsN |journal=Nature Microbiology |language=en |volume=7 |issue=10 |pages=1686–1701 |doi=10.1038/s41564-022-01206-9 |pmid=36123441 |pmc=7613929 |issn=2058-5276}}</ref>
Along with other bacterial actin homologs such as MreB, ParM, and MamK, these proteins suggest that eukaryotic actin has a common ancestry. Like the other bacterial actins, FtsA binds ATP and can form actin-like filaments.<ref name="pmid22473211">{{cite journal | vauthors = Szwedziak P, Wang Q, Freund SM, Löwe J | title = FtsA forms actin-like protofilaments | journal = The EMBO Journal | volume = 31 | issue = 10 | pages = 2249–60 | date = May 2012 | pmid = 22473211 | doi = 10.1038/emboj.2012.76 | pmc=3364754}}</ref> The FtsA-FtsA interface has been defined by structural as well as genetic analysis.<ref name="pmid22111832">{{cite journal | vauthors = Pichoff S, Shen B, Sullivan B, Lutkenhaus J | title = FtsA mutants impaired for self-interaction bypass ZipA suggesting a model in which FtsA's self-interaction competes with its ability to recruit downstream division proteins | journal = Molecular Microbiology | volume = 83 | issue = 1 | pages = 151–67 | date = Jan 2012 | pmid = 22111832 | doi = 10.1111/j.1365-2958.2011.07923.x | pmc=3245357}}</ref> Although present in many diverse Gram-positive and Gram-negative species, FtsA is absent in actinobacteria and cyanobacteria. FtsA also is structurally similar to PilM, a type IV pilus ATPase.<ref name="pmid21596754">{{cite journal | vauthors = Karuppiah V, Derrick JP | title = Structure of the PilM-PilN inner membrane type IV pilus biogenesis complex from Thermus thermophilus | journal = The Journal of Biological Chemistry | volume = 286 | issue = 27 | pages = 24434–42 | date = Jul 2011 | pmid = 21596754 | doi = 10.1074/jbc.M111.243535 | pmc=3129222| doi-access = free }}</ref>
== Function == FtsA is required for proper cytokinesis in bacteria such as ''Escherichia coli'', ''Caulobacter crescentus'', and ''Bacillus subtilis''. Originally isolated in a screen for ''E. coli'' cells that could divide at 30˚C but not at 40˚C,<ref name="Kohiyama1966">{{cite journal | vauthors = Kohiyama M, Cousin D, Ryter A, Jacob F | title = Mutants thermosensibles d'Escherichia coli K12 | journal = Annales de l'Institute Pasteur | volume = 110 | issue = 4 | pages = 465–86 | date = April 1966 }}</ref> FtsA stands for "'''f'''ilamentous '''t'''emperature '''s'''ensitive '''A'''". Many thermosensitive alleles of ''E. coli ftsA'' exist, and all map in or near the ATP binding pocket. Suppressors that restore normal function map either to the binding pocket or to the FtsA-FtsA interface.<ref name="pmid25213228">{{cite journal | vauthors = Herricks JR, Nguyen D, Margolin W | title = A thermosensitive defect in the ATP binding pocket of FtsA can be suppressed by allosteric changes in the dimer interface | journal = Molecular Microbiology | volume = 94 | issue = 3 | pages = 713–27 | date = Nov 2014 | pmid = 25213228 | doi = 10.1111/mmi.12790 | pmc=4213309}}</ref> thumb|FtsA active site with ADP bound (PDB 7Q6G). FtsA, like actin and its homologs, is an ATPase. While the exact catalytic mechanism of FtsA is not fully understood, glutamic acid Glu14 in the FtsA of ''Escherichia coli'' is indicated as a key residue involved in catalysis, as mutation of this residue impairs the enzyme's ability to hydrolyze ATP, in addition to halting phospholipid vesicle remodeling and Z-ring assembly ''in vivo.''<ref>{{Cite journal |last1=Morrison |first1=Josiah J. |last2=Conti |first2=Joseph |last3=Camberg |first3=Jodi L. |date=2022-03-01 |title=Assembly and architecture of Escherichia coli divisome proteins FtsA and FtsZ |journal=Journal of Biological Chemistry |volume=298 |issue=3 |article-number=101663 |doi=10.1016/j.jbc.2022.101663 |doi-access=free |pmid=35104502 |issn=0021-9258|pmc=8897712 }}</ref> During cell division, FtsA self-polymerizes to form long, antiparallel double filaments that then localize to the cytokinetic ring formed by FtsZ (Z ring).<ref name=":0" /> This occurs via a conserved C-terminal amphipathic helix, forming an "A ring" in the process.<ref name="pmid15752196">{{cite journal | vauthors = Pichoff S, Lutkenhaus J | title = Tethering the Z ring to the membrane through a conserved membrane targeting sequence in FtsA | journal = Molecular Microbiology | volume = 55 | issue = 6 | pages = 1722–34 | date = Mar 2005 | pmid = 15752196 | doi = 10.1111/j.1365-2958.2005.04522.x | doi-access = free }}</ref> Removal of this helix results in the formation of very long and stable polymer bundles of FtsA in the cell that do not function in cytokinesis.<ref name="pmid22111832"/> Another essential division protein, ZipA, also tethers the Z ring to the membrane and exhibits overlapping function with FtsA. FtsZ, FtsA and ZipA together are called the proto-ring because they are involved in a specific initial phase of cytokinesis.<ref name="pmid23740256">{{cite journal | vauthors = Rico AI, Krupka M, Vicente M | title = In the beginning, Escherichia coli assembled the proto-ring: an initial phase of division | journal = The Journal of Biological Chemistry | volume = 288 | issue = 29 | pages = 20830–6 | date = Jul 2013 | pmid = 23740256 | doi = 10.1074/jbc.R113.479519 | pmc=3774354| doi-access = free }}</ref> Another subdomain of FtsA (2B) is required for interactions with FtsZ, via the conserved C-terminus of FtsZ.<ref name="pmid22473211"/> Other FtsZ regulators including MinC and ZipA bind to the same C terminus of FtsZ. Finally, subdomain 1C, which is in a unique position relative to MreB and actin, is required for FtsA to recruit downstream cell division proteins such as FtsN.<ref name="pmid15387815">{{cite journal | vauthors = Rico AI, García-Ovalle M, Mingorance J, Vicente M | title = Role of two essential domains of Escherichia coli FtsA in localization and progression of the division ring | journal = Molecular Microbiology | volume = 53 | issue = 5 | pages = 1359–71 | date = Sep 2004 | pmid = 15387815 | doi = 10.1111/j.1365-2958.2004.04245.x | doi-access = free }}</ref><ref name="pmid22328664">{{cite journal | vauthors = Busiek KK, Eraso JM, Wang Y, Margolin W | title = The early divisome protein FtsA interacts directly through its 1c subdomain with the cytoplasmic domain of the late divisome protein FtsN | journal = Journal of Bacteriology | volume = 194 | issue = 8 | pages = 1989–2000 | date = Apr 2012 | pmid = 22328664 | doi = 10.1128/JB.06683-11 | pmc=3318488}}</ref>
Although FtsA is essential for viability in ''E. coli'', it can be deleted in ''B. subtilis''. ''B. subtilis'' cells lacking FtsA divide poorly but still survive. Another FtsZ-interacting protein, SepF (originally named YlmF; {{UniProt|O31728}}), is able to replace FtsA in ''B. subtilis'', suggesting that SepF and FtsA have overlapping functions.<ref name="pmid16796675">{{cite journal | vauthors = Ishikawa S, Kawai Y, Hiramatsu K, Kuwano M, Ogasawara N | title = A new FtsZ-interacting protein, YlmF, complements the activity of FtsA during progression of cell division in Bacillus subtilis | journal = Molecular Microbiology | volume = 60 | issue = 6 | pages = 1364–80 | date = Jun 2006 | pmid = 16796675 | doi = 10.1111/j.1365-2958.2006.05184.x | s2cid = 19570920 }}</ref>
An allele of FtsA called FtsA* (R286W) is able to bypass the normal requirement for the ZipA in ''E. coli'' cytokinesis.<ref name="pmid12634424">{{cite journal | vauthors = Geissler B, Elraheb D, Margolin W | title = A gain-of-function mutation in ftsA bypasses the requirement for the essential cell division gene zipA in Escherichia coli | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 7 | pages = 4197–202 | date = Apr 2003 | pmid = 12634424 | doi = 10.1073/pnas.0635003100 | pmc=153070| doi-access = free | bibcode = 2003PNAS..100.4197G }}</ref> FtsA* also causes cells to divide at a shorter cell length than normal, suggesting that FtsA may normally receive signals from the septum synthesis machinery to regulate when cytokinesis can proceed.<ref name="pmid17322202">{{cite journal | vauthors = Geissler B, Shiomi D, Margolin W | title = The ftsA* gain-of-function allele of Escherichia coli and its effects on the stability and dynamics of the Z ring | journal = Microbiology | volume = 153 | issue = Pt 3 | pages = 814–25 | date = Mar 2007 | pmid = 17322202 | doi = 10.1099/mic.0.2006/001834-0 | doi-access = free | pmc=4757590}}</ref> Other FtsA*-like alleles have been found, and they mostly decrease FtsA-FtsA interactions.<ref name="pmid22111832"/> Oligomeric state of FtsA is likely important for regulating its activity, its ability to recruit the later cell division proteins <ref name="pmid22111832"/> and its ability to bind ATP.<ref name="pmid25213228"/> Other cell division proteins of ''E. coli'', including FtsN and the ABC transporter homologs FtsEX, seem to regulate septum constriction by signaling through FtsA,<ref name="pmid27503875">{{cite journal | vauthors = Du S, Pichoff S, Lutkenhaus J | title = FtsEX acts on FtsA to regulate divisome assembly and activity | journal = Proc Natl Acad Sci USA | volume = 113 | issue = 34 | pages = 5052–5061 | date = Aug 2016 | pmid = 27503875| doi = 10.1073/pnas.1606656113 | pmc=5003251| doi-access = free | bibcode = 2016PNAS..113E5052D }}</ref><ref name="pmid25496259">{{cite journal | vauthors = Pichoff S, Du S, Lutkenhaus J | title = The bypass of ZipA by overexpression of FtsN requires a previously unknown conserved FtsN motif essential for FtsA-FtsN interaction supporting a model in which FtsA monomers recruit late cell division proteins to the Z ring | journal = Molecular Microbiology | volume = 95 | issue = 6 | pages = 971–987 | date = Mar 2015 | pmid = 25496259| doi = 10.1111/mmi.12907 | pmc=4364298}}</ref> and the FtsQLB subcomplex is also involved in promoting FtsN-mediated septal constriction.<ref name="pmid25496050">{{cite journal | vauthors = Tsang MJ, Bernhardt TG | title = A role for the FtsQLB complex in cytokinetic ring activation revealed by an ftsL allele that accelerates division | journal = Molecular Microbiology | volume = 95 | issue = 6 | pages = 924–944 | date = Mar 2015 | pmid = 25496050| doi = 10.1111/mmi.12905 | pmc=4414402}}</ref><ref name="pmid25496160">{{cite journal | vauthors = Liu B, Persons L, Lee L, de Boer P | title = Roles for both FtsA and the FtsBLQ subcomplex in FtsN-stimulated cell constriction in Escherichia coli | journal = Molecular Microbiology | volume = 95 | issue = 6 | pages = 945–970 | date = Mar 2015 | pmid = 25496160| doi = 10.1111/mmi.12906 | pmc=4428282}}</ref> thumb|''E. coli'' cells producing FtsA-GFP, which localizes to the cell division site. FtsA binds directly to the conserved C-terminal domain of FtsZ.<ref name="pmid11847116">{{cite journal |vauthors=Pichoff S, Lutkenhaus J |title=Unique and overlapping roles for ZipA and FtsA in septal ring assembly in Escherichia coli. |journal=EMBO Journal |volume=21 |issue=4 |pages=685–93 |year=2002 |pmid=11847116 |pmc=125861 |doi=10.1093/emboj/21.4.685 }}</ref><ref name="pmid22473211"/> This FtsA-FtsZ interaction is likely involved in regulating FtsZ polymer dynamics. In vitro, ''E. coli'' FtsA disassembles FtsZ polymers in the presence of ATP, both in solution, as FtsA* <ref name="pmid19297332">{{cite journal | vauthors = Beuria TK, Mullapudi S, Mileykovskaya E, Sadasivam M, Dowhan W, Margolin W | title = Adenine nucleotide-dependent regulation of assembly of bacterial tubulin-like FtsZ by a hypermorph of bacterial actin-like FtsA | journal = The Journal of Biological Chemistry | volume = 284 | issue = 21 | pages = 14079–86 | date = May 2009 | pmid = 19297332 | doi = 10.1074/jbc.M808872200 | pmc=2682856| doi-access = free }}</ref> and on supported lipid bilayers.<ref name="pmid24316672">{{cite journal | vauthors = Loose M, Mitchison TJ | title = The bacterial cell division proteins FtsA and FtsZ self-organize into dynamic cytoskeletal patterns | journal = Nature Cell Biology | volume = 16 | issue = 1 | pages = 38–46 | date = Jan 2014 | pmid = 24316672 | doi = 10.1038/ncb2885 | pmc=4019675}}</ref> ''E. coli'' FtsA itself does not assemble into detectable structures except when on membranes, where it forms dodecameric minirings that often pack in clusters and bind to single FtsZ protofilaments.<ref>{{cite journal | vauthors = Krupka M, Rowlett VW, Morado D, Vitrac H, Schoenemann K, Liu J, Margolin W | title = Escherichia coli FtsA forms lipid-bound minirings that antagonize lateral interactions between FtsZ protofilaments | journal = Nature Communications | volume = 8 | article-number = 15957 | date = July 2017 | pmid = 28695917 | pmc = 5508204 | doi = 10.1038/ncomms15957 | bibcode = 2017NatCo...815957K }}</ref> In contrast, FtsA* forms arcs on lipid membranes but rarely closed minirings, supporting genetic evidence that this mutant has a weaker FtsA-FtsA interface.<ref name="pmid22111832" /> When bound to the membrane, FtsA*-like mutants, which also can form double-stranded filaments, enhance close lateral interactions between FtsZ protofilaments, in contrast to FtsA, which keeps FtsZ protofilaments apart.<ref>{{cite journal | vauthors = Schoenemann KM, Krupka M, Rowlett VW, Distelhorst SL, Hu B, Margolin W | title = Gain-of-function variants of FtsA form diverse oligomeric structures on lipids and enhance FtsZ protofilament bundling | journal = Molecular Microbiology | volume = 109 | issue = 5 | pages = 676–693 | date = September 2018 | pmid = 29995995 | pmc = 6181759 | doi = 10.1111/mmi.14069 | first8 = William }}</ref> As FtsZ protofilament bundling may be important for promoting septum formation, a switch from an FtsA-like to an FtsA*-like conformation during cell cycle progression may serve to turn on septum synthesis enzymes (FtsWI) as well as condense FtsZ polymers, setting up a positive feedback loop. In support of this model, the cytoplasmic domain of FtsN, which activates FtsWI in ''E. coli'' and interacts directly with the 1C subdomain of FtsA, switches FtsA from the miniring form to the double stranded filament form on lipid surfaces in vitro.<ref>{{cite journal | vauthors = Nierhaus T, McLaughlin SH, Bürmann F, Kureisaite-Ciziene D, Maslen SL, Skehel JM, Yu CW, Freund SM, Funke LF, Chin JW, Löwe J | title = Bacterial divisome protein FtsA forms curved antiparallel double filaments when binding to FtsN | journal = Nature Microbiology | volume = 7 | pages = 1686–1701 | date = September 2022 | issue = 10 | pmid = 36123441 | doi = 10.1038/s41564-022-01206-9 | pmc = 7613929 }}</ref> These double filaments of ''E. coli'' FtsA are antiparallel, indicating that they themselves do not treadmill like FtsZ filaments.
Although E. coli FtsA has been the most extensively studied, more is becoming understood about FtsA proteins from other species. FtsA from ''Streptococcus pneumoniae'' forms helical filaments in the presence of ATP,<ref name="pmid15660997">{{cite journal |vauthors=Lara B, Rico AI, Petruzzelli S, Santona A, Dumas J, Biton J, Vicente M, Mingorance J, Massidda O |title=Cell division in cocci: localization and properties of the Streptococcus pneumoniae FtsA protein |journal=Molecular Microbiology |volume=55 |issue=3 |pages=699–711 |year=2005 |pmid=15660997 |doi=10.1111/j.1365-2958.2004.04432.x |url=https://iris.unitn.it/bitstream/11572/187538/1/Lara%20et%20al_%20Mol%20Microbiol_2005.pdf |hdl=11572/187538 |s2cid=42834683 |hdl-access=free }}</ref> but no interactions with FtsZ in vitro have been reported yet. FtsA colocalizes with FtsZ in ''S. pneumoniae'', but also is required for FtsZ ring localization, in contrast to ''E. coli'' where FtsZ rings remain localized upon inactivation of FtsA. FtsA from ''Staphylococcus aureus'' forms actin-like filaments similar to those of FtsA from ''Thermotoga maritima''.<ref name="pmid27872183">{{cite journal | vauthors = Mura A, Fadda D, Perez A, Danforth ML, Musu D, Rico AI, Krupka M, Denapaite D, Tsui HT, Branny P, Vicente M, Winkler ME, Margolin W, Massidda O | title = Roles of the essential protein FtsA in cell growth and division in Streptococcus pneumoniae | journal = Journal of Bacteriology | volume = 199 | issue = 3 | pages = e00608-16 | date = February 2017 | pmid = 27872183 | doi = 10.1128/JB.00608-16 | pmc = 5237122 | doi-access = free }}</ref> In addition, ''S. aureus'' FtsA enhances the GTPase activity of FtsZ. In a liposome system, FtsA* stimulates FtsZ to form rings that can divide liposomes, mimicking cytokinesis in vitro.<ref name="pmid23776220">{{cite journal |vauthors=Osawa M, Erickson HP |title=Liposome division by a simple bacterial division machinery |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=110 |issue=27 |pages=11000–4 |year=2013 |pmid=23776220 |pmc=3703997 |doi=10.1073/pnas.1222254110 |doi-access=free |bibcode=2013PNAS..11011000O }}</ref>
== Structure == Several crystal structures for FtsA are known, including a structure for ''E. coli'' FtsA.<ref>{{cite journal | vauthors = Nierhaus T, McLaughlin SH, Bürmann F, Kureisaite-Ciziene D, Maslen SL, Skehel JM, Yu CW, Freund SM, Funke LF, Chin JW, Löwe J | title = Bacterial divisome protein FtsA forms curved antiparallel double filaments when binding to FtsN | journal = Nature Microbiology | volume = 7 | pages = 1686–1701 | date = September 2022 | issue = 10 | pmid = 36123441 | doi = 10.1038/s41564-022-01206-9 | pmc = 7613929 }}</ref> Compared to MreB and eukaryotic actin, the subdomains are rearranged, and the 1B domain is swapped out for the SHS2 "1C" insert.<ref name="pmid22473211"/><ref name="pmid24746687">{{cite journal | vauthors = Fujita J, Maeda Y, Nagao C, Tsuchiya Y, Miyazaki Y, Hirose M, Mizohata E, Matsumoto Y, Inoue T, Mizuguchi K, Matsumura H | title = Crystal structure of FtsA from Staphylococcus aureus | journal = FEBS Letters | volume = 588 | issue = 10 | pages = 1879–85 | date = May 2014 | pmid = 24746687 | doi = 10.1016/j.febslet.2014.04.008 | doi-access = free | bibcode = 2014FEBSL.588.1879F }}</ref><ref name="pmid11032797"/><ref name="pmid15281131">{{cite journal | vauthors = Anantharaman V, Aravind L | title = The SHS2 module is a common structural theme in functionally diverse protein groups, like Rpb7p, FtsA, GyrI, and MTH1598/TM1083 superfamilies | journal = Proteins | volume = 56 | issue = 4 | pages = 795–807 | date = September 2004 | pmid = 15281131 | doi = 10.1002/prot.20140 | s2cid = 9140384 }}</ref>
== References == {{reflist}}
Category:Bacterial proteins Category:Cytoskeleton