[論文紹介] Asgardアーキアのゲノムはアクチンを制御するプロフィリンをコードしている (Genomes of Asgard archaea encode profilins that regulate actin)
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論文紹介 (2018) Genomes of Asgard archaea encode profilins that regulate actin Asgardアーキアのゲノムはアクチンを制御するプロフィリンをコードしている ※なぜか文字が表示されない場合は全画面表示や保存をすると表示されるようです。
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[論文紹介] Asgardアーキアのゲノムはアクチンを制御するプロフィリンをコードしている (Genomes of Asgard archaea encode profilins that regulate actin)
- 1. Asgardアーキアのゲノムは アクチンを制御するプロフィリンをコードしている 2018.10.23 PMID: 30283132 M1 永田 祥平 LETTER https://doi.org/10.1038/s41586-018-0548-6 Genomes of Asgard archaea encode profilins that regulate actin Caner Akıl1,2 & Robert C. Robinson1,2,3 * The origin of the eukaryotic cell is unresolved1,2 . Metagenomics sequencing has recently identified several potential eukaryotic gene homologues in Asgard archaea3,4 , consistent with the hypothesis that the eukaryotic cell evolved from within the Archaea domain. However, many of these eukaryotic-like sequences are highly divergent and the organisms have yet to be imaged or cultivated, which brings into question the extent to which these archaeal proteins represent functional equivalents of their eukaryotic counterparts. Here we show that Asgard archaea encode functional profilins and thereby establish that this archaeal superphylum has a regulated actin cytoskeleton, one of the hallmarks of the eukaryotic cell5 . Loki profilin-1, Loki profilin-2 and Odin profilin adopt the typical profilin fold and are able to interact with rabbit actin—an interaction that involves proteins from species that diverged more than 1.2 billion years ago6 . Biochemical experiments reveal that mammalian actin polymerizes in the presence of Asgard profilins; however, Loki, Odin and Heimdall profilins impede pointed-end elongation. These archaeal profilins also retard the spontaneous nucleation of actin filaments, an effect that is reduced in the presence of phospholipids. Asgard profilins do not interact with polyproline motifs and the profilin–polyproline interaction therefore probably evolved later in the Eukarya lineage. These results suggest that Asgard archaea possess a primordial, polar, profilin-regulated actin system, which may be localized to membranes owing to the sensitivity of Asgard profilins to phospholipids. Because Asgard archaea are also predicted to encode potential eukaryotic-like genes involved in membrane-trafficking and endocytosis3,4 , imaging is now necessary to elucidate whether these organisms are capable of generating eukaryotic-like membrane dynamics that are regulated by actin, such as are observed in eukaryotic cell movement, podosomes and endocytosis. Recently, metagenomics studies have identified genes from Asgard archaea (Heimdall, Loki, Thor and Odin) that are homologous to eukaryotic genes that encode machineries involved in membrane ca d Verrucosispora sediminis Actinomadura sp. Saccharopolyspora flava Streptomyces avermitilis Nocardia soli 1 /LC7/MgLB
- 2. 2 要旨 真核細胞の起源は明らかになっていない。メタゲノミクス配列決定により，真核細胞がアーキアドメイン内 から進化したという仮説と一致して，Asgardアーキアにおけるいくつかの真核生物と相同と思われる遺伝 子が同定された。しかし，これらの真核生物様配列の多くは高度に多様化しており，生物個体は未だ映像化 または培養されていないので，これらのアーキアタンパク質が真核生物のタンパク質とどの程度の機能的同 等性を示すかが問題となっている。 そこで我々は，Asgardアーキアが機能的なプロフィリンをコードし，それによってこのアーキア上門が 真核細胞の特徴の一つである制御されたアクチン細胞骨格を有することを示す。 ① Loki profilin-1，Loki profilin-2，Odin profilinは典型的なプロフィリンフォールドを採用し，ウサギア クチンと相互作用することができた。(12億年以上前に分岐した種のタンパク質が相互作用する！) ② 生化学的実験により，哺乳動物のアクチンはAsgardプロフィリンの存在下で重合することが明らかに なった。(しかし，Loki，OdinおよびHeimdallのプロフィリンは尖った伸びを妨げる。) ③ これらの古代のプロフィリンは，リン脂質の存在下で減少するアクチンフィラメントの自発的な核形成を 遅らせる。Asgardプロフィリンはポリプロリンモチーフと相互作用しないため，プロフィリン-ポリプロ リン相互作用はおそらく後の真核系統において進化した。 これらの結果は，Asgardアーキアが，Asgardプロフィリンのリン脂質に対する感受性のために，膜に局在 化する可能性のある初期の極性，プロフィリン制御アクチン系を有することを示唆している。 Asgard アーキアは，膜輸送およびエンドサイトーシスに関与する潜在的な真核生物様遺伝子もコードする と予想されているので，これらの生物が真核生物の細胞運動，ポドソームおよびエンドサイトーシスにおい て観察されるような，アクチンによって調節される真核生物様膜動態を生成することができるかどうかを解 明する必要があり，イメージングが必要と考えられる。 背景 結果
- 3. 3 背景：生物の分類 -3ドメイン説とその終焉- http://oceanexplorer.noaa.gov/explorations/06fire/background/microbiology/microbiology.html Adapted from Woese et al. 1990. Woeseらによる3ドメイン説の提唱 地球上の細胞型生命は真核生物と原核生物に大別され，原核生物はバクテリアとアーキアに 分類される
- 4. 4 背景：生物の分類 -3ドメイン説とその終焉- Williams T a, Foster PG, Cox CJ, Embley TM. An archaeal origin of eukaryotes supports only two primary domains of life. Nature. 2013;504(7479):231‒6. ion now debatedis whethercorecomponents of the eukaryotic eage descend from a common ancestor shared with Archaea, ree-domains tree14 (Fig. 1), which is also often called the ‘uni- or‘treeof life’15–17 ,or from withintheArchaea,asproposed by ost hypotheses for eukaryotic origins2 . The archaeal-host sce- the greatest phylogenetic support is the eocyte hypothesis18 , poses a sister-group relationship between eukaryotes and the span of time, the accumulation of multiple substitutions in protein sequences might have erased any signal that would relationship between archaeal and eukaryotic core genes to lished21 . However, more recent simulations and empirical s gest that there are reasons to be cautiously optimistic that thi case: functional constraints vary across real DNA and protein so that sites evolve at different rates22–25 . Fast-evolving sites ll and MolecularBiosciences, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK. 2 Departmentof Life Sciences, Natural History Museum,London SW7 5BD, UK. 3 Cen Euryarchaeota Eocytes/Crenarchaeota Eukaryota Bacteria Eocytes/Crenarchaeota Paraphyletic Archaea Three-domains hypothesis Eocyte hypothesis Thaumarchaeota Aigarchaeota Korarchaeota Euryarchaeota Eocytes/Crenarchaeota Eukaryota Bacteria Euryarchaeota Eocytes/Crenarchaeota Monophyletic Archaea Thaumarchaeota Aigarchaeota Korarchaeota TACK TACK a b ompeting hypotheses for the origin of the eukaryotic host cell. d three-domains tree14 depicts cellular life divided into three major ic groups or domains: the Bacteria, Archaea and Eukaryota—the enting the host lineage, sometimes also called the nuclear or plasmic lineage5 , that acquired the mitochondrial endosymbiont. he Archaea and Eukaryota are most closely related to each other y share a common ancestor that is not shared with Bacteria. ed eocyte tree recovers the host-cell lineage nested within the Archaea as a sister group to the eocytes (which Woese et al.14 call Crenarchaeota); this implies that, on the basis of the small set of c there are only two primary domains of life—the Bacteria and the Ar modern formulation shown here the eocyte hypothesis implies tha relative of the eukaryotic nuclear lineage is one, or all, of the TAC which include newly discovered relatives of the eocytes/Crenarcha Both trees have been traditionally rooted on the bacterial stem, con some published analyses5–8 . アーキア 近年，真核生物はアーキアの１系統であると考えられるようになってきた。 ➤ 3ドメイン仮説 ➤ エオサイト仮説 (2ドメイン) →最新の手法で慎重に系統樹を構築した結果，真核生物はアーキアの系統内に入った。
- 5. 5 背景： 真核生物に最も近いアーキア の発見 ➤ 真核生物の特徴を多く持つアーキア（ロキアー キオータ）の発見 (2015年) (上部) Spang A, Saw JH, Jørgensen SL, Zaremba-Niedzwiedzka K, Martijn J, Lind AE, et al. Complex archaea that bridge the gap between prokaryotes and eukaryotes. Nature. 2015;521(7551):173‒9. (下部) Zaremba-Niedzwiedzka K, Caceres E, Saw J, Backstrom D, Juzokaite L, Vancaester E, et al. Asgard arcahea illuminates the origin of eukaryotic cellular complexity. Nat Publ Gr. Nature Publishing Group; 2017;541(7637):353‒8. ARTICLERESEARCH a 0.1 Lokiarchaeum sp. GC14_75 Odinarchaeote LCB_4 Heimdallarchaeote AB_125 Thorarchaeote W O R_83 Heimdallarchaeote LC_3 ThorarchaeoteAB_25 Heimdallarchaeote LC_2 Thorarchaeote W OR_45 LokiarchaeoteCR_4 LC LCB CR WOR RP AB, 0.25 m.b.s.f. AB, 0.5 m.b.s.f. AB, 1.25 m.b.s.f. AB, 1.75 m.b.s.f. b c 0.3 Thorarchaeote WOR_83 Odinarchaeote LCB_4 Bathyarchaeota Lokiarchaeum sp. GC14_75 Thorarchaeote AB_25 Korarchaeota Aigarchaeota Heimdallarchaeote LC_3 Heimdallarchaeote AB_125 Euryarchaeota Odinarchaeote RP_19 Thaumarchaeota Heimdallarchaeote LC_2 Lokiarchaeote CR_4 Crenarchaeota 91 74 100 100100 82 84 100 100 87 42 100 46 100 85 28 52 97 100 41 94 100 Eukarya 0.2 Heimdallarchaeote LC_2 Lokiarchaeum sp. GC14_75 Aigarchaeota Heimdallarchaeote LC_3 Thorarchaeote WOR_45 Thaumarchaeota Crenarchaeota Odinarchaeote LCB_4 Eukarya Korarchaeota Thorarchaeote WOR_83 Lokiarchaeote CR_4 Heimdallarchaeote AB_125 Bathyarchaeota Thorarchaeote AB_25 1 10.94 1 1 1 1 1 0.99 0.54 1 0.99 1 10.98 1 0.77 0.94 TACK d Lokiarchaeum sp. GC14_75 Lokiarchaeote CR_4 Odinarchaeote LCB_4 Thorarchaeote AB_25 Thorarchaeote WOR_45 Thorarchaeote WOR_83 Heimdallarchaeote AB_125 Heimdallarchaeote LC_2 Heimdallarchaeote LC_3 Information processing Cell division/ cytoskeleton DNApolymerase,ε-like TopoisomeraseIB RNApolymerase,Afused RNApolymerase,subunitG (rpb8) RibosomalproteinL22e RibosomalproteinL28e/Mak16 Tubulins* Actin-relatedprotein(ARP-like) Conservedlokiactins Gelsolin-domainproteinProfilin Endosomal sorting Ubiquitin system Trafficking machinery Ost complex ARP2/3complex,subunit4-like ESCRT-I:steadinessboxdomain ESCRT-I:Vps28-like ESCRT-II:Vps25-like ESCRT-II:EAP30domain ESCRT-III:Vps2/24/46-like ESCRT-III:Vps20/32/60-like Ubiquitin-domainprotein Ubiquitin-activatingE1candidates E2-likeubiquitinconjugatingprotein ExpansionofsmallGTPases Longin-domainprotein EukaryoticRLC7familiyprotein TRAPP-domainprotein Sec23/24-likeprotein WD40–Armadillogenecluster Arrestin-domain RibophorinI OST3/OST6-like STT3-like Heimdallarchaeota Lokiarchaeota Odinarchaeota Thorarchaeota Figure 1 | Identification and phylogenomics of Asgard archaea. a, Maximum-likelihood tree, inferred with RAxML and PROTCATLG model, based on metagenomic contigs containing conserved ribosomal proteins (see Methods) revealing the Asgard superphylum. Slow, non- parametric maximum-likelihood bootstrap support values above 50 and 90 are indicated with empty and filled circles, respectively. Abbreviations of the sites mentioned are as follows: LC, Loki’s Castle; CR, Colorado River aquifer (USA); LCB, Lower Culex Basin (Yellowstone National Park, sequences inferred with RAxML and GTRGAMMA model (c) showing high support for the phylogenetic affiliation between Asgard archaea and eukaryotes (support values in red). a–c, Scale bars indicate number of substitutions per site. Numbers at branches refer to Bayesian posterior probabilities (b) and slow non-parametric maximum-likelihood bootstrap values (c). Trees were rooted with Euryarchaeota + DPANN (a, b) and with Bacteria (c). Branch length value corresponding to cut branch in c is ➤ さらに近いアーキア群：Asgard上門の発見 (2017年) 数多くの「真核生物特異的」なタンパク質を保有 Asgardアーキア: Ordin, Loki, Thor, Heimdall 真核生物→ メタゲノム配列ベースで，数多くの真核生物特異的な遺伝子を持つアーキア群が発見され た。
- 6. 6 本研究のコンセプト メタゲノム解析より，真核特異的なはずの遺伝子を持つアーキアが発見された。 ① 真核生物の遺伝子とその配列は似ていても，構造的・機能的にも同等なのか？ ② そもそもサンプル中の真核遺伝子がアーキアメタゲノムにコンタミしたのでは？ でも.. → タンパク質立体構造を決定し，その機能を明らかにする！
- 7. 7 背景：原核生物と真核生物の違い.. 原核細胞 真核細胞 核 ない ある 膜で囲まれた細胞内小器官 ない ある 原核細胞 真核細胞 細胞膜 細胞質 DNA 核様体 核 リボソーム 0.1-10 µm 10-100 µm 細胞内骨格 ない ある Kuroda H. 生命現象と現実社会の比較論 (第7回講義). 2015. これまで，真核生物の大きな特徴は細胞内骨格であるとされてきた。
- 8. 8 背景：プロフィリンはアクチンの重合を制御する アクチン結合タンパク質 単量体のG-アクチンと1:1で結合し，成長しているフィラメントへ G-アクチンが取り込まれるのを防ぐ。 ➤ アクチン ➤ プロフィリン Kuroda H. 生命現象と現実社会の比較論 (第7回講義). 2015. G-アクチン F-アクチン +端, B端, 反矢尻端: アクチンが重合する側 -端, P端, 矢尻端: アクチンが解離する側 緑: アクチン 青: プロフィリン
- 9. 9 本論文の流れ Fig. 1：Asgardプロフィリンの構造を決定し，Asgardアーキアが真のプ ロフィリンをコードしていることを示す。 Fig. 2：Asgardプロフィリンが哺乳類アクチンと相互作用し，アクチン重 合を制御する機能を持っていることを示す。 Fig. 3：Asgardプロフィリンと哺乳類アクチンの共結晶構造を決定し， Asgardアーキアと真核生物が共通のプロフィリン-アクチン相互作用様式 を持つことを示す。 Fig. 4：Asgardプロフィリンとアクチンの相互作用もリン脂質によって制 御されることを示し，アクチン系が膜に局在している可能性を示唆する。
- 10. 10 Asgardアクチンは真核アクチンと同様の機能・特性を持つと考えられる。 Extended Data Fig.1 Asgardアーキアはアクチンを保有する ホモログ (相同) = 同一の祖先から進化したもの nd are here referred to as the ‘Asgard actins’. b, Models of the Asgard ctins. The Asgard actins were modelled using I-TASSER. The ‘C-score’ s a confidence score for estimating the quality of predicted models, which is typically in the range of −5 to 2 and in which a high C-score ignifies a model with a high confidence. Template modelling scores TM-scores’) range between 0 and 1, and values greater than 0.5 indicate models of the correct topology and a value of 1 indicates an exact match. The TM-score and r.m.s.d. are estimated by linear regression, and the stimated errors are the root-mean-squared TM-score or r.m.s. deviations. ➤ Asgardアクチンの構造モデリング 哺乳類 (真核生物) アクチン Asgardアクチン ① 真核アクチンと非常に類似した構造を取る RMSD: 平均二乗偏差（Root Mean Square Deviation） タンパク質構造の非類似性や誤りの指標 TM-score: モデル評価の指標．0.0-1.1の値を取り，1.1 は正解構造との肝炎一致を示す。 LETTERRESEARCH Extended Data Fig. 1 | Asgard actins. a, Phylogenetic tree of the polymerizing actin fold. This phylogenetic tree reveals that the variability observed between the Asgard and eukaryotic actins is approximately similar in magnitude to the variability found within bacterial MreBs and lower than that observed within bacterial FtsAs or ParMs, which indicates a probable conservation in function between the Asgard and and are here referred to as the ‘Asgard actins’. b, Models of the Asgard actins. The Asgard actins were modelled using I-TASSER. The ‘C-score’ is a confidence score for estimating the quality of predicted models, which is typically in the range of −5 to 2 and in which a high C-score signifies a model with a high confidence. Template modelling scores (‘TM-scores’) range between 0 and 1, and values greater than 0.5 indicate MreB: アクチンアナログ 桿状バクテリアの形状を制御 (球状のバクテリアにはない) ➤ Asgardアクチンと真核アクチン・他のアクチン 相同タンパク質との構造ベースの系統関係 ParM: 構造的にはアクチンに類似 FtsA: チューブリンホモログ Asgardアクチン 真核生物アクチン ② Asgardアクチンは他の原核生物が持つア クチン相同タンパク質と異なり，真核生物 アクチンと非常に近接した系統を形成する 真核アクチンと別系統を構成することから，真核のコンタミである可能性は低い
- 11. 11 プロフィリンとアクチンの各配列相同性一覧 Supplementary Table 1 Supplementary Table 1. Pairwise percentage sequence identities of actins and profilins. a, Actins. From sequence identity LokiActin, OdinActin, ThorActin and HeimdallActin are referred to a: アクチン b: プロフィリン ① Asgardアクチンはヒトアクチンと58-60%と 高い配列相同性を示す。 ② Asgardプロフィリンとヒトプロフィリン は11-17%の配列相同性しか示さない。 Asgardプロフィリンの特性・機能を調べる必要がある。 ヒト-Asgard間→ Asgardアクチンはヒトアクチンと非常に類似しているため機能的に同等と考えられるが, プロフィリンはあまり似てないため..
- 12. 12 Asgardメタゲノムはプロフィリンをコードする ical profilin fold and are able to interact with rabbit actin—an eraction that involves proteins from species that diverged more n 1.2 billion years ago6 . Biochemical experiments reveal that mmalian actin polymerizes in the presence of Asgard profilins; wever, Loki, Odin and Heimdall profilins impede pointed-end by actin, such as are observed in eukaryotic cell movement, podosomes and endocytosis. Recently, metagenomics studies have identified genes from Asgard archaea (Heimdall, Loki, Thor and Odin) that are homologous to eukaryotic genes that encode machineries involved in membrane 2 c N C Loki loop Loki profilin-1 Human profilin N C N Loki profilin-2 from rabbit α-actin complex Loki loop N C from rabbit α-actin complex Odin profilin f N C b a 77 99 82 83 99 83 84 61 69 100 e N C Loki loop from rabbit α-actin complex Loki profilin-1 d Verrucosispora sediminis Actinomadura sp. Saccharopolyspora flava Streptomyces avermitilis Nocardia soli Frankia sp. Thermus Thermophilus Candidatus Thorarchaeota 1 Candidatus Thorarchaeota 2 Zea mays Arabidopsis thaliana Dictyostelium discoideum Monosiga brevicollis Schizosaccharomyces pombe Saccharomyces cerevisiae Neurospora crassa Galdieria sulphuraria Monodelphis domestica Homo sapiens Xenopus tropicalis Danio rerio Tetrahymena pyriformis Paramecium tetraurelia Noctiluca scintillans Plasmodium falciparum Toxoplasma gondii Trepomonas sp. Spironucleus salmonicida Leishmania braziliensis Trypanosoma brucei Entamoeba histolytica Porphyra umbilicalis Strongylocentrotus purpuratus Lottia gigantea Thor profilin Odin profilin Heimdall profilin Loki profilin-3 Loki profilin-1 Loki profilin-2 1 Roadblock/LC7/MgLBEukaryoticprofilins Asgard profilins 1 | Asgard metagenomes encode genuine profilins. a, Schematic he structure of Loki profilin-1. The partially disordered extended p (Loki loop) is indicated by a dotted line. N and C indicate the pective termini. Data collection and refinement statistics are found upplementary Table 2a. b, The structure of human profilin-1 for mparison (RCSB Protein Data Bank (PDB) code: 1FIL). c, Profilin logenetic tree of Asgard and eukaryotic profilins calculated from structure-based sequence alignment using the Asgard profilin structures in this figure. Protein sequences of the Roadblock/LC7/MgLB group are used as an outgroup because their structures have similar topologies to profilins. Sequence and PDB accession codes used in the alignment are given in Supplementary Table 1b. d–f, Loki profilin-1 (d), Loki profilin-2 (e) and Odin profilin (f) structures taken from the rabbit α-actin complex structures. Details are found in Fig. 3. • Asgardプロフィリンの構造を決定し真のプロフィリンであることを示した。 • 特徴的な構造 (Loki loop)の存在を確認した。 Fig.1 a: Asgardプロフィリン単体の立体構造 b: ヒトプロフィリン単体の立体構造 d,e,f: 哺乳類アクチン複合体構造のAsgardプロフィリン部分 typical profilin fold and are able to interact with rabbit actin—an interaction that involves proteins from species that diverged more than 1.2 billion years ago6 . Biochemical experiments reveal that mammalian actin polymerizes in the presence of Asgard profilins; however, Loki, Odin and Heimdall profilins impede pointed-end by actin, such as are observed in eukaryotic cell movement, podosomes and endocytosis. Recently, metagenomics studies have identified genes from Asgard archaea (Heimdall, Loki, Thor and Odin) that are homologous to eukaryotic genes that encode machineries involved in membrane c N C Loki loop Loki profilin-1 Human profilin N C N Loki profilin-2 from rabbit α-actin complex Loki loop N C from rabbit α-actin complex Odin profilin f N C b a 77 99 82 83 99 83 84 61 69 100 e N C Loki loop from rabbit α-actin complex Loki profilin-1 d Verrucosispora sediminis Actinomadura sp. Saccharopolyspora flava Streptomyces avermitilis Nocardia soli Frankia sp. Thermus Thermophilus Candidatus Thorarchaeota 1 Candidatus Thorarchaeota 2 Zea mays Arabidopsis thaliana Dictyostelium discoideum Monosiga brevicollis Schizosaccharomyces pombe Saccharomyces cerevisiae Neurospora crassa Galdieria sulphuraria Monodelphis domestica Homo sapiens Xenopus tropicalis Danio rerio Tetrahymena pyriformis Paramecium tetraurelia Noctiluca scintillans Plasmodium falciparum Toxoplasma gondii Trepomonas sp. Spironucleus salmonicida Leishmania braziliensis Trypanosoma brucei Entamoeba histolytica Porphyra umbilicalis Strongylocentrotus purpuratus Lottia gigantea Thor profilin Odin profilin Heimdall profilin Loki profilin-3 Loki profilin-1 Loki profilin-2 1 Roadblock/LC7/MgLBEukaryoticprofilins Asgard profilins Fig. 1 | Asgard metagenomes encode genuine profilins. a, Schematic of the structure of Loki profilin-1. The partially disordered extended loop (Loki loop) is indicated by a dotted line. N and C indicate the respective termini. Data collection and refinement statistics are found in Supplementary Table 2a. b, The structure of human profilin-1 for comparison (RCSB Protein Data Bank (PDB) code: 1FIL). c, Profilin phylogenetic tree of Asgard and eukaryotic profilins calculated from structure-based sequence alignment using the Asgard profilin structures in this figure. Protein sequences of the Roadblock/LC7/MgLB group are used as an outgroup because their structures have similar topologies to profilins. Sequence and PDB accession codes used in the alignment are given in Supplementary Table 1b. d–f, Loki profilin-1 (d), Loki profilin-2 (e) and Odin profilin (f) structures taken from the rabbit α-actin complex structures. Details are found in Fig. 3. ➤ Asgardプロフィリンとヒトプロフィリンの立体構造 ➤ Asgardプロフィリンの系統関係 →外群 真核生物の プロフィリン Asgard プロフィリン Asgardプロフィリンは真核プロフィリンと 関連しつつも独立した系統を構成する。 部分的に乱れたループ
- 13. 13 Asgardプロフィリンは哺乳類アクチンの重合を制御する LETTERRESEARCH Odin profilin 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) Heimdall profilin Human profilin versus Odin profilin 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) Actin (2 μM) 8 μM 16 μM 32 μM 64 μM 128 μM Thor profilin 0 10,000 20,000 JYIM01000447 JYIM01000257 Found in archaea Only bacteria Loki profilins Only Asgard Only eukaryotes 8792949487909192919294748292928891919074878596 Loki profilin-3 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) a b c d e f g h i Human profilin Loki profilin-1 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) Loki profilin-2 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) Thorprofilin Fig. 2 | Asgard profilins modulate polymerization of mammalian actin in vitro. a, Pyrene–actin polymerization profiles of 2 µM rabbit α-actin profilin. Thor profilin was not observed to have profilin activity and is not included in subsequent discussions of Asgard profilins. h, Comparison of Asgardプロフィリンは哺乳類アクチンを調節する上で機能的であることを示した。 →Asgardアーキアにはプロフィリン制御のアクチン系が存在することを示唆。 →Thorはプロフィリン活性なしと判断 Fig.2 手法：ピレン-アクチン重合アッセイ アクチン重合反応に取り込まれると蛍光の増強が起こるピレン標識アクチンを用いて，アクチンの重合/脱重合反応を蛍光で測定 ヒトとOdinのプロフィン性能比較 実線: ヒト，紫: Odin プロフィン ヒトプロフィリン8倍投入して同程度の性能 縦軸: ↑アクチンが重合 ↓プロフィンによって重合が制御 (抑制)されている ゲルゾリン (gelsolin): アクチン繊維を切断し，その末端に 留まることでその後のアクチン重合を阻害 (キャップ)する。 ※ゲルソリン-アクチンは片側 (P端)からしか重合できない。線: ウサギαアクチンのみ 線: ウサギαアクチン + ⃝⃝プロフィリン a-f: 赤: アクチンのみで重合開始 青: 非蛍光アクチンシード存在下で重合開始 黒: ゲルゾリン結合状態の非蛍光アクチンシード存在下で重合開始 d, e: OrdinとHeimdallプロフィリンはゲルゾリン-アクチン のP端からの伸長を防ぐ能力が弱い。
- 14. 14 Loki profilin遺伝子とその周辺領域 maintenance and function, including trafficking, N-glycosylation, ribosomes, endosomal sorting complexes required for transport, the ubiquitination system, and cytoskeletal processes that include actin and eukaryotic profilins (7–24%) (Supplementary Table 1b). T questions about their authenticity. To address this issue, explored the properties of Asgard profilin-like proteins. Odin profilin 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) Human profi versus Odin pr 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) Actin (2 μM) 8 μM 16 μM 32 μM 64 μM 128 μM Thor profilin 0 10,000 20,000 JYIM01000447 JYIM01000257 Found in archaea Only bacteria Loki profilins Only Asgard Only eukaryotes 8792949487909192919294748292928891919074878596 Loki profilin-3 0 50 100 150 0 20 40 60 80 Time (min) Fluorescence(AU) e f g h i 0 50 100 150 200 250 Time (min) 0 50 100 150 Time (min) 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) 0 50 100 150 200 250 Time (min) 0 50 100 150 200 250 Time (min) Thorprofilin Fig. 2 | Asgard profilins modulate polymerization of mammalian actin in vitro. a, Pyrene–actin polymerization profiles of 2 µM rabbit α-actin (dashes, 10% pyrene–actin) or 2 µM rabbit α-actin with 128 µM human profilin-1 (dots) either initiated alone (red), initiated in the presence of 0.3 µM non-fluorescent actin seeds (blue), or initiated in the presence of 0.3 µM non-fluorescent gelsolin-capped actin seeds (black). b–f, Polymerization profiles as in a, using the specified Asgard profilin at 256 µM (instead of 128 µM human profilin-1). Loki profilin-3 and, to a lesser extent, Loki profilin-1 showed a marked increase in fluorescence on mixing with pyrene–actin; however, their profiles appear to be typical for Asgard profilins, albeit superimposed upon the initial increases. The basis of the increase is unknown, but we speculate that it may be due to oligomer formation. Titrations and expansions of the lag phase regions are in Extended Data Figs. 2, 3. g, Pyrene–actin polymerization profiles of 2 µM rabbit α-actin titrated with increasing concentrations of Thor profilin. Thor profilin was not observed to have profilin activity included in subsequent discussions of Asgard profilins. h, Com the inhibition of actin nucleation in the pyrene–actin assay reve human profilin-1 (solid lines; red 2 µM, green 4 µM, orange 32 approximately eightfold more potent than Odin profilin (purple 16 µM, dots 64 µM, dots-and-dashes 256 µM). Actin control (2 shown as a solid black line. Comparisons for other Asgard profi shown in Extended Data Fig. 3b. i, Schematic alignment of the p contigs that contain the Loki profilin-1 and Loki profilin-2 gene Lines connect homologous genes, with nucleotide percentage id indicated below (Supplementary Table 3b). Genes with homolo previously found in archaea are coloured blue, and genes curren to Asgard archaea are coloured red. Genes with homologues tha been found to date in bacteria or eukaryotes are coloured black respectively. The Loki profilins are in green. AU, arbitrary units Fig.2 Loki profilin-1のcontig→ Loki profilin-2のcontig→ Lokiプロフィリン遺伝子 (緑色)とその遺伝子周辺領域含めて全体的に相同性が認められる。 → Loki profilin-1, 2は2つの異なるLokiアーキア系統であり，真核生物のコンタミではないことを確認。
- 15. 15 Asgardプロフィリンと哺乳類アクチン複合体の共結晶構造 LETTER RESEARCH of Loki profilin-1 on the two ends of actin filaments. Low concentra- tions of human profilin-1 or Loki profilin-1 did not slow elongation at the barbed ends (Extended Data Figs. 2, 3). Higher concentrations of human profilin-1 and Loki profilin-1 showed small decreases in elon- gation rates (Fig. 2a, b), consistent with dynamic barbed end binding by profilin10 , but at least tenfold more archaeal profilin than human pro- filin was required to achieve similar effects (Extended Data Figs. 2, 3). Gelsolin–actin seeds grow only at the pointed ends. As with lower concentrations of human profilin-1, high concentrations of Loki profilin-1 partially inhibited the elongation of pointed ends (Fig. 2a, b). Spontaneous polymerization of actin monomers depends on a slow, rate-limiting nucleation step. Loki profilin-1 slowed the time course of actin polymerization, but required concentrations that were more than 30 times higher than those required when using human profilin-1 (Fig. 2a, b). Because barbed ends elongate under these conditions, this experiment demonstrates that high concentrations of Loki profilin-1 inhibit spontaneous nucleation; presumably, the higher concentrations of Loki profilin-1 that are required are due to its low affinity for rabbit α-actin. These data suggest that, despite the divergence between Lokiarchaeota and eukaryotes, Loki profilin-1 is partially functional in regulating mammalian actin in vitro, which in turn indicates a profilin-regulated actin system in these archaea. To demonstrate that the Loki profilin-1 activity is not an isolated case that may be due to eukaryotic contamination in the metagenomes, we produced five other potential Asgard profilins for the in vitro assays (Extended Data Fig. 3c). Loki profilin-2 shares 87% and 91% identity with Loki profilin-1 at amino acid and nucleotide levels, respectively. Comparison of their parent contigs reveals global homology and a high percentage of typical archaeal genes (Fig. 2i). Thus, Loki profilin-1 and Loki profilin-2 appear to come from two related strains of Lokiarchaeota.Lokiprofilin-2displayedsimilaractivitytoLokiprofilin-1 in the polymerization assay (Fig. 2c). Heimdall profilin showed a lesser, but measurable, ability to inhibit spontaneous actin nucleation (Fig. 2d), whereas Odin profilin (Fig. 2e) and Loki profilin-3 (Fig. 2f) showed higher activity relative to Loki profilin-1. The presence of the Loki loop in Loki profilin-1 and Loki profilin-2, but not in Loki profilin-3, indicates possible functional divergence (Extended Data Fig. 5a). Thor profilin displayed no measurable ability to inhibit actin nuclea- a b c Loki profilin-1 Loki profilin-2 Loki loop Loki loop Actin 1 1 2 2 3 4 3 4 C N C N Odin profilin 24 C N d 180 LETTER RESEARCH of Loki profilin-1 on the two ends of actin filaments. Low concentra- tions of human profilin-1 or Loki profilin-1 did not slow elongation at the barbed ends (Extended Data Figs. 2, 3). Higher concentrations of human profilin-1 and Loki profilin-1 showed small decreases in elon- gation rates (Fig. 2a, b), consistent with dynamic barbed end binding by profilin10 , but at least tenfold more archaeal profilin than human pro- filin was required to achieve similar effects (Extended Data Figs. 2, 3). Gelsolin–actin seeds grow only at the pointed ends. As with lower concentrations of human profilin-1, high concentrations of Loki profilin-1 partially inhibited the elongation of pointed ends (Fig. 2a, b). Spontaneous polymerization of actin monomers depends on a slow, rate-limiting nucleation step. Loki profilin-1 slowed the time course of actin polymerization, but required concentrations that were more than 30 times higher than those required when using human profilin-1 (Fig. 2a, b). Because barbed ends elongate under these conditions, this experiment demonstrates that high concentrations of Loki profilin-1 inhibit spontaneous nucleation; presumably, the higher concentrations of Loki profilin-1 that are required are due to its low affinity for rabbit α-actin. These data suggest that, despite the divergence between Lokiarchaeota and eukaryotes, Loki profilin-1 is partially functional in regulating mammalian actin in vitro, which in turn indicates a profilin-regulated actin system in these archaea. To demonstrate that the Loki profilin-1 activity is not an isolated case that may be due to eukaryotic contamination in the metagenomes, we produced five other potential Asgard profilins for the in vitro assays (Extended Data Fig. 3c). Loki profilin-2 shares 87% and 91% identity with Loki profilin-1 at amino acid and nucleotide levels, respectively. Comparison of their parent contigs reveals global homology and a high percentage of typical archaeal genes (Fig. 2i). Thus, Loki profilin-1 and Loki profilin-2 appear to come from two related strains of Lokiarchaeota.Lokiprofilin-2displayedsimilaractivitytoLokiprofilin-1 in the polymerization assay (Fig. 2c). Heimdall profilin showed a lesser, but measurable, ability to inhibit spontaneous actin nucleation (Fig. 2d), whereas Odin profilin (Fig. 2e) and Loki profilin-3 (Fig. 2f) showed higher activity relative to Loki profilin-1. The presence of the Loki loop in Loki profilin-1 and Loki profilin-2, but not in Loki profilin-3, indicates possible functional divergence (Extended Data Fig. 5a). Thor profilin displayed no measurable ability to inhibit actin nuclea- tion (Fig. 2g). Odin profilin was approximately eightfold less potent in inhibiting spontaneous actin nucleation, relative to human profilin-1 (Fig. 2h). Odin profilin and Heimdall profilin showed very weak abili- ties to prevent pointed-end elongation in the gelsolin–actin seed assay. These data demonstrate that actin-regulating profilins are present in a b c Loki profilin-1 Loki profilin-2 Loki loop Loki loop Actin 1 1 2 2 3 4 3 4 C N C N Odin profilin Actin 2 24 4 C N d 180 Fig.3 Asgardアーキアと真核生物が共通のプロフィリン-アクチン相互作用様式を持つことを示し た。 ➤ Lokiプロフィリン-1 地熱環境に生息Odinのプロフィリンは最もコンパクトな構造を取る filin was requ Gelsolin–ac concentrati profilin-1 pa Spontaneou rate-limiting of actin poly than 30 time (Fig. 2a, b). B experiment inhibit spont of Loki profi α-actin. Th Lokiarchaeo in regulatin profilin-regu To demon that may be d produced fiv (Extended D with Loki pr Comparison percentage o and Loki pr Lokiarchaeot in the polym but measurab whereas Od higher activ loop in Loki indicates po Thor profilin tion (Fig. 2g) inhibiting sp (Fig. 2h). Od ties to preven These data d three branch collected from (Loki and He Tobetteru determined t and Odin pr and Loki pro a similar ori b c Loki profilin-1 Loki profilin-2 Loki loop Loki loop 1 1 3 3 C N C N Human profilin Odin profilin Actin 1 1 2 2 3 4 3 4 C N C N d Fig. 3 | The structures of the Loki profilin-1, Loki profilin-2 and Odin profilin complexes with rabbit α-actin. a, Back and front views of the structure of the Loki profilin-1–rabbit α-actin complex. Rabbit α-actin is shown as a surface and Loki profilin-1 is shown in schematic concentrati profilin-1 pa Spontaneou rate-limiting of actin poly than 30 time (Fig. 2a, b). B experiment inhibit spont of Loki profi α-actin. Th Lokiarchaeo in regulatin profilin-regu To demon that may be d produced fiv (Extended D with Loki pr Comparison percentage o and Loki pr Lokiarchaeot in the polym but measurab whereas Od higher activ loop in Loki indicates po Thor profilin tion (Fig. 2g) inhibiting sp (Fig. 2h). Od ties to preven These data d three branch collected from (Loki and He Tobetteru determined t and Odin pr and Loki pro a similar ori (Fig. 1b, d, e, Loki profilin (Extended D b c Loki profilin-1 Loki profilin-2 Loki loop Loki loop 1 1 3 3 C N C N Human profilin Odin profilin Actin 1 1 2 2 3 4 3 4 C N C N d Fig. 3 | The structures of the Loki profilin-1, Loki profilin-2 and Odin profilin complexes with rabbit α-actin. a, Back and front views of the structure of the Loki profilin-1–rabbit α-actin complex. Rabbit α-actin is shown as a surface and Loki profilin-1 is shown in schematic representation. b, The Loki profilin-2–rabbit α-actin complex. c, The Odin profilin–rabbit α-actin complex. d, Structure of the published ➤ Lokiプロフィリン-2 ➤ ヒトプロフィリン-1➤ Odinプロフィリン ウサギαアクチン → 数字はサブドメインを示す (比較用) ・LokiプロフィリンのC末端ヘリックスは，ヒトプロフィリン-1と比較して，アクチンサブドメイン1上の結合部位からわずかにずれる。 ・Lokiループはアクチンとの結合で整列し，アクチンサブドメイン3の表面に近接して存在する。
- 16. 16 Asgardプロフィリンと真核プロフィリンの差異 LETTERRESEARCH 20 40 60 80 orescence(AU) 20 40 60 80 orescence(AU) 20 40 60 80orescence(AU) 20 40 60 80 orescence(AU) K69 K90 K71 K58 K60 K71 K60 i j k l e f g h Asn9 Tyr6 Human profilin Trp3 Trp31 Tyr139 His133 Leu134 N Polyproline N-helix C-helix C Ile32 Ile5 Ile8 Asp11 Lys129 Leu130 Leu133 N-helix Loki profilin-1 C-helix a b c d Val32 Ile5 Ile8 Asp11 Lys129 Leu130 Leu133 N-helix Loki profilin-2 C-helix Ile28 Leu3 Leu6 Arg9 Gln114 Leu115 Ile118 N-helix Odin profilin C-helix Fig.4 芳香族アミノ酸：フェニルアラニン (Phe)，トリプトファン (Trp)，ヒスチジン (His)，チロシン (Tyr)，etc. ➤ プロフィリン上のポリプロリン結合領域 真核生物のプロフィリンは，プロフィリンのN末端およびC末端ヘリックスの間にある芳香族残基との相互作用により， ポリプロリンモチーフに結合することによって，アクチンフィラメント核形成および伸長機械に組み込まれる。 Asgardプロフィリンには芳香族残基によるポリプロリン結合溝が存在しない。 →Asgardメタゲノムには真核生物様のポリプロリンリッチなアクチン核形成また は伸長タンパク質の遺伝子が存在せず，一致する結果。 →プロフィリン‒ポリプロリン間の相互作用は，真核生物ドメイン系統で後に進化したのでは。 AsgardプロフィリンがAsgardメタゲノムに由来し，真核生物のコンタミではないことを裏付け る。
- 17. 17 Asgardプロフィリンと真核プロフィリンの差異 LETTERRESEARCH 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) 0 50 100 150 200 250 0 20 40 60 80 Time (min) Fluorescence(AU) Actin (2 μM) hP (10 μM) PIP2 (20 μM) PIP2 (40 μM) PIP2 (160 μM) K69 K90 K71 K58 K60 K71 K60 i j k l e f g h Actin (2 μM) LokiP1 (50 μM) PIP2 (50 μM) PIP2 (100 μM) PIP2 (200 μM) Actin (2 μM) LokiP2 (50 μM) PIP2 (50 μM) PIP2 (100 μM) PIP2 (200 μM) Actin (2 μM) OdinP (50 μM) PIP2 (50 μM) PIP2 (100 μM) PIP2 (200 μM) Asn9 Tyr6 Human profilin Trp3 Trp31 Tyr139 His133 Leu134 N Polyproline N-helix C-helix C Ile32 Ile5 Ile8 Asp11 Lys129 Leu130 Leu133 N-helix Loki profilin-1 C-helix a b c d Val32 Ile5 Ile8 Asp11 Lys129 Leu130 Leu133 N-helix Loki profilin-2 C-helix Ile28 Leu3 Leu6 Arg9 Gln114 Leu115 Ile118 N-helix Odin profilin C-helix Fig. 4 | Asgard profilins do not bind to polyproline motifs but are sensitive to phospholipids. a, The polyproline-binding site on human profilin-1 (PDB code: 2PAV)12 . The polyproline ligand is shown in black, with the respective termini labelled as N or C, and the residues on human profilin-1 that interact with the polyproline motif are labelled in blue. b–d, Equivalent residues to those shown in a, from the Loki profilin-1 (b), Loki profilin-2 (c) and Odin profilin (d) structures. In the structures of Asgard profilins, the N- and C-terminal helices are tightly in e, for structures of Loki profilin-1 (f), Loki profilin-2 (g) and Odin profilin (h) complexes with actin, with the basic residues indicated. Views rotated by 180° are shown in Extended Data Fig. 7a. i, Pyrene–actin polymerization profiles of rabbit α-actin (2 µM, orange) supplemented with human profilin-1 (hP, 10 µM, pink) and subsequently with increasing concentrations of PtdIns-(4,5)-P2(1,2-dipalmitoyl) (blue), a soluble version of PIP2. j–l, Similar polymerization profiles to those shown in i, for Loki profilin-1 (LokiP1, j), Loki profilin-2 (LokiP2, k) and Odin profilin Fig.4 ホスファチジルイノシトール-4,5-ビホスフェート (PtdIns (4,5) P2 ; PIP2)：真核細胞膜でアクチンを調節するための 機能性リン脂質 e-f: タンパク質の電荷分析. 青: 正電荷，赤: 負電荷 ➤ ヒトプロフィリン ➤ Lokiプロフィリン-1 ➤ Lokiプロフィリン-2 ➤ Odinプロフィリン-1 塩基性残基 i-l: PIP2とプロフィリンのアクチン重合阻害能との関連 Asgardプロフィリンとアクチンの相互作用もリン脂質によって制御される。 → 膜に局在している可能性を示唆。 PIP2はAsgardプロフィリンと弱く相互作用し，プロフィリンによるアクチン重合阻害を抑制する
- 18. 18 総括 まとめ/掲載理由 本論文では，これまで配列レベルでしか存在が予測されていなかったAsgardアーキアプロ フィリンが実際に真核生物プロフィリンと酷似した立体構造を取ることを明らかにし，真 核生物のアクチンと相互作用して重合を制御することを示した。 これらは真核生物が持つ細胞骨格系の原型と考えられ，真核生物がアーキアから進化した ことを強く裏付けた。 感想 • 構造決定タンパク質選定の目の付け所が良い。 • Asgardアーキアのアクチンの立体構造・相互作用はどうなっているのか。 • 核の起源についても気になるところではある。 organisms — an archaeal host cell1–3 and a bacterium from which eukaryotic organelles called mitochondria emerged4 . Some insights into the biological properties of the host have come from the closest known archaeal rela- tives of eukaryotes, the Asgard superphylum5,6 . The genomes of organisms belonging to this archaeal group encode a suite of proteins typically involved in functions or processes thought to be eukaryote-specific. The func- tions of these ‘eukaryotic genes’ in Asgard archaea have been elusive, but in a paper in Nature, Akıl and Robinson7 provide evidence that some of them encode proteins that are structurally and functionally similar to their eukaryotic counterparts. Apart from their nucleus and energy- producing mitochondria, eukaryotic cells are characterized by a complex internal sys- tem of membrane-bound compartments (the endomembrane system), and by a dynamic network of proteins such as actin, called the cytoskeleton. The latter gives the cells their shape and structure, but is also involved in a variety of cellular processes specific to eukary- otes8 . These features are thought to have been present in the last common ancestor of all eukaryotes, which lived about 1.8 billion years ago9 , but no life forms have been found that represent an intermediate between eukaryotes and their bacterial and archaeal ancestors. The seemingly sudden emergence of cellu- lar complexity in the eukaryotic lineage is a conundrum for evolutionary biologists. Several of the proteins produced by Asgard archaea are evolutionarily related to proteins that in eukaryotes modulate complex cellular processes5,6 . The identification of these pro- teins raised the question of whether Asgard archaea have some primitive versions of certain eukaryotic properties. If they do, it would suggest that the last archaeal ancestor of eukaryotes already displayed a certain — albeit probably limited — degree of cellular ota and Heimdallarchaeota)5,6 is based solely on metagenomics analyses. The cells have yet to be observed under a microscope, and have not been cultured in vitro. Nevertheless, Akıl and Robinson were determined to gain insight into the properties of Asgard proteins related totheeukaryoticproteinsactinandprofilin.In eukaryotes, profilin regulates the polymeriza- tion of actin into filaments of the cytoskeleton. These filaments have pivotal roles in processes that include vesicle and organelle movement, cell-shape formation and phagocytosis8 , in whichcellsingestforeignparticlesorothercells. To produce Asgard profilins, Akıl and Robinson expressed these proteins in the bac- terium Escherichia coli using a circular DNA Asgardprofilinscouldinteractwitheukaryotic actins. Remarkably, despite being separated by 2 billion to 3 billion years of evolution9 , several of the Asgard profilins bound to mammalian actinandregulateditspolymerizationkinetics. Asgard and mammalian profilins seem to have similar effects on mammalian actin, although the Asgard proteins act less efficiently. These results suggest that Asgard archaea harbour a profilin-regulated actin cytoskeleton — a cel- lular feature generally regarded as a defining characteristic of eukaryotic cells (Fig. 1). The inference of a primitive dynamic actin cytoskeleton in Asgard archaea sheds light on the biological properties of the ancestor of eukaryotes. In eukaryotic cells, the energy Figure 1 | Cellular complexity along the tree of life. The Eukarya (organisms whose cells harbour DNA in a nucleus) are thought to have arisen from a merger between their last archaeal ancestor and a bacterium. In addition to a nucleus, eukaryotes have several characteristics that are thought to separate them from archaea, including: a complex internal system of membranes called endomembranes; a structural feature called the actin cytoskeleton, the dynamics of which are regulated by the protein profilin; and energy-producing organelles called mitochondria, which arose from the bacterial partner. But Akıl and Robinson7 provide evidence that members of the Asgard superphylum — an extant group of archaea thought to be related to eukaryotes — harbour a primitive profilin-regulated actin cytoskeleton. If the last archaeal ancestor of eukaryotes had this feature, it might have enabled the cell to wrap around its presumed bacterial partner. In addition, it is possible that Asgard archaea and the last archaeal ancestor of eukaryotes carry primitive endomembrane systems. (Cells and cellular features are not drawn to scale.) Bacterial partner Eukarya Last archaeal ancestor of eukaryotes Asgard archaea Other archaea Mitochondrion Nucleus Actin cytoskeleton Primitive endomembrane system Primitive actin cytoskeleton DNA Cytoskeleton- mediated interaction? Profilin Endomembrane system Eme L, Ettema TJG. The eukaryotic ancestor shapes up. Nature. 2018;562(7727):352‒3.
- 19. 19 Fig. 1補足データ Extended Data Fig. 2 Appendix LETTER RESEARCH Extended Data Fig. 2 | Titration data. Titration data for the polymerization profiles that are shown in Fig. 2a–f.
- 20. 20 Fig. 2補足データ Extended Data Fig. 3 Appendix LETTERRESEARCH b: Fig. 2h補足 a: Fig. 2a-f補足
- 21. 21 構造に基づく配列アライメント Extended Data Fig. 5 LETTERRCH Extended Data Fig. 5 | See next page for caption. Appendix a: プロフィリン，b: アクチン Lokiループ ↓ アクチン結合サイトは真核とアーキアで同じ領域にあるが， アミノ酸配列はあまり保存されていない。 Odinアクチンの翻訳開始位置。 フレームシフトの可能性あり。