カルモジュリン

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藤井 哉
東京大学医学系研究科神経生化学教室
DOI:10.14931/bsd.4597 原稿受付日:2015年8月7日 原稿完成日:2015年9月30日
担当編集委員:和田 圭司(国立研究開発法人国立精神・神経医療研究センター)

英:calmodulin

 カルモジュリンは148アミノ酸残基、分子量約16.7kDa、酸性のCa2++結合タンパク質であり、それぞれ2つのEFハンドドメインからなるN末側ドメインとC末側ドメインがリンカーでつながったダンベル様構造をしている。カルモジュリンは、酵母、植物、昆虫からヒトまで真核生物に発現しており、特に脊椎動物の中では高い保存性を示す。Ca2+と結合することで、Ca2+バッファーとして働くほか、下流のタンパク質に結合して活性などを調節し、Ca2+センサーとしてCa2+シグナル伝達の中でも非常に重要な役割を果たす。特に脳においては、Ca2+シグナル伝達をコントロールする中心的な役割を担い、神経突起形成、軸索伸展、シナプス形成、シナプス可塑性、記憶・学習など様々な機能に関わる。

カルモジュリン
3CLN.pdb
カルモジュリンEF-handの結晶構造[1]
Identifiers
Symbol efhand
Pfam PF00036
InterPro IPR002048
PROSITE PDOC00018
SCOP 1osa
SUPERFAMILY 1osa
OPM protein 1djx
CDD cd00051
Calmodulin 1
Identifiers
Symbols CALM1; CALML2; CAMI; CPVT4; DD132; LQT14; PHKD; caM
External IDs OMIM114180 MGI88251 HomoloGene134804 GeneCards: CALM1 Gene
EC number 2.7.11.19
Orthologs
Species Human Mouse
Entrez 801 640703
Ensembl ENSG00000198668 ENSMUSG00000001175
UniProt P62158 P62204
RefSeq (mRNA) NM_001166106 NM_009790
RefSeq (protein) NP_008819 NP_033920
Location (UCSC) Chr 14:
90.4 – 90.41 Mb
Chr 12:
101.44 – 101.45 Mb
PubMed search [1] [2]
Calmodulin 2
Identifiers
Symbols CALM2; CAMII; LQT15; PHKD; PHKD2; caM
External IDs OMIM114182 MGI103250 HomoloGene134804 GeneCards: CALM2 Gene
EC number 2.7.11.19
Orthologs
Species Human Mouse
Entrez 805 640703
Ensembl ENSG00000143933 ENSMUSG00000036438
UniProt P62158 P62204
RefSeq (mRNA) NM_001305624 NM_007589
RefSeq (protein) NP_001292553 NP_031615
Location (UCSC) Chr 2:
47.16 – 47.18 Mb
Chr 17:
87.83 – 87.85 Mb
PubMed search [3] [4]
Calmodulin 3
Identifiers
Symbols CALM3; HEL-S-72; PHKD; PHKD3
External IDs OMIM114183 MGI103249 HomoloGene134804 GeneCards: CALM3 Gene
EC number 2.7.11.19
Orthologs
Species Human Mouse
Entrez 808 640703
Ensembl ENSG00000160014 ENSMUSG00000019370
UniProt P62158 P62204
RefSeq (mRNA) NM_005184 NM_007590
RefSeq (protein) NP_005175 NP_031616
Location (UCSC) Chr 19:
46.6 – 46.61 Mb
Chr 7:
17.5 – 17.51 Mb
PubMed search [5] [6]

発見

 1970年、Kakiuchiらは、ラット抽出物中の環状ヌクレオチドフォスフォジエステラーゼ活性がCa2+により制御されることを報告し[2]、このCa2+依存性を担う調節因子を見出した[3][4]。また、同じ1970年に独立してCheungは環状ヌクレオチドフォスフォジエステラーゼの活性が精製の過程で減弱することから、精製の過程で分離される分画より活性化因子を発見し報告した[5]

 1973年にTeoとWangらはウシの心臓からこの活性化因子を精製し[6]、これらの別々に発見された因子の正体が同一のCa2+結合タンパク質であることを示した[7][8]

 その後、トロポニンCに特性が類似したタンパク質であることが示され[9] [10]、アミノ酸配列が決定され[11]、分光学的解析によってCa2+結合に伴って構造が変化することが示された[12] [13] [14]。その呼び名は研究グループによって、activator protein, modulator protein, Ca2+dependent regulator protein(CDR)、Phosphodiesterase Activating Factor(PAF)などさまざまに呼ばれたが、1970年代末にcalmodulinという名称が付けられた[15][16]

構造

 カルモジュリンは148残基のアミノ酸からなる、分子量約16.7kDaのタンパク質である。1985年にCa2+存在下のウシ由来カルモジュリンのX線結晶構造が解かれ、原子レベルでの構造が明らかになった[17]。Ca2+と結合する4つのヘリックス・ループ・ヘリックス構造のEFハンドモチーフを持ち、2つずつがそれぞれペアとなって球状のN末側ドメイン、C末側ドメインを形成し、その間をリンカーがつながったダンベル様の構造をしている。それぞれの球状のドメインの大きさは約25×20×20 Åであり、分子全体としては長軸が約65 Åの長さである[17]

サブファミリー

 ヒトのCalmodulin1、Calmodulin2、Calmodulin3は同一のアミノ酸配列のタンパク質をコードしており、それぞれ染色体上の14q24-q31、2p21.1-p21.3、19q13.2-q13.3に位置する(表1[18]

表1. ヒトカルモジュリン遺伝子
タンパク質名称 NCBI遺伝子情報 NCBI mRNA情報 (RefSeq) HUGO遺伝子命名法委員会 (HGNC) Allen mouse brain
Calmodulin1 801 NM_006888 CALM1 12098
Calmodulin2 805 NM_001743 CALM2 12099
Calmodulin3 808 NM_005184 CALM3 12100

 その他、酵母植物昆虫からヒトまで真核生物に発現しており、特に脊椎動物の中では高い保存性を示す。

機能

 カルモジュリンは脳内で10~100 µmol/lの濃度で発現しており[19]、細胞内で上昇したCa2+と結合し、Ca2+バッファーとして働くのに加え、様々なカルモジュリン結合タンパク質と結合して生理機能を発揮する(表2)。

エフェクタータンパク質

 カルモジュリンの主要な機能は、細胞内のCa2+濃度の変化を感知し、カルモジュリン結合タンパク質の機能制御を通じて、細胞機能を制御(活性化、抑制)することであり、その具体的な効果はターゲットとなる下流のタンパク質によって様々に異なる。多くはCa2+依存性がありCa2+/カルモジュリンと結合するが、Ca2+と結合していないカルモジュリンと結合するタンパク質や、Ca2+非依存的に結合するタンパク質も存在する。

 Ca2+に対する親和性の違いから、C末側ドメインはN末側ドメインに比べCa2+に対する親和性が高く、in vitroでトリプシン処理により得られたN末側/C末側ドメインのCa2+親和性をpH 7.5, 100 mM KCl, 25 ℃の条件下で測定した場合には、それぞれ1.5~100 μM、0.4~10 μMである[20]。Ca2+依存的な結合の場合、カルモジュリンがCa2+と結合することで、疎水性領域が露出し、ターゲットとなるタンパク質のカルモジュリン結合ドメインにある疎水性のアミノ酸残基と相互作用する。この疎水性アミノ酸残基の位置によって、幾つかのもシーフに分類される[21][22][23]

 また、カルモジュリンはリン酸化[24]糖化[25]メチル化[11]など翻訳後修飾を受け、機能を調節することが知られている[26][27]

表2. カルモジュリン結合タンパク質
タンパク質名称 参考文献
環状ヌクレオチド代謝酵素 ホスホジエステラーゼ [2]
アデニル酸シクラーゼ [28][29][30]
膜タンパク質 細胞膜カルシウムATPアーゼ (plasma membrane Ca2+-ATPase; PMCA) [31][32][33]
NMDA型グルタミン酸受容体 [34]
代謝活性型グルタミン酸受容体 [35][36]
L型カルシウムチャネル [37][38]
P/Q型カルシウムチャネル [39]
IP3受容体 [40]
リン酸化酵素 ミオシン軽鎖キナーゼ (MLCK) [41][42][43][44]
Ca2+/カルモジュリン依存性タンパク質キナーゼI (CaMKI) [45]
Ca2+/カルモジュリン依存性タンパク質キナーゼII (CaMKII) [46][47]
Ca2+/カルモジュリン依存性タンパク質キナーゼIV (CaMKIV) [48]
Ca2+/カルモジュリン依存性タンパク質キナーゼキナーゼ (CaMKK) [49][50]
ホスホリラーゼキナーゼ [51]
脱リン酸化酵素 カルシニューリン [52][53]
細胞骨格系タンパク質 MAP2 [54]
タウ [54]
アデューシン [55]
ミオシン [56][57][58][59]
一酸化窒素合成酵素 [60][61]
熱ショックタンパク質70/90 [62][63]

神経系での機能

神経回路の発達

 神経突起形成[64][65]軸索伸展[66][67][68]、シナプスの形成[69]などを通して、神経回路の発達に関わる。

 例えば、発生期に神経細胞が軸索を伸展し標的となる細胞に投射して神経回路を構築する際には、軸索の先端部は成長円錐を形成し、細胞外の軸索ガイダンス分子などのシグナルに応じて誘引されたり反発されたりすることで、その伸展する方向を制御している。アフリカツメガエル脊髄神経細胞やニワトリ後根神経節細胞を用いた実験などから、ガイダンス分子としてネトリン1[70][71]SEMA3A[72][73]をはじめさまざま知られており、これらは受容体を介して局所的なCa2+上昇を引き起こし、その濃度や局在によってカルモジュリンは異なるターゲットを活性化し、成長円錐の誘引や反発をコントロールしている。

シナプス可塑性、記憶・学習

 脳機能において、カルモジュリンは、そのターゲットとなるCaMKII、カルシニューリン、アデニル酸シクラーゼなどの下流のエフェクター酵素の制御を通してのシナプス可塑性記憶学習の制御に関して不可欠な役割を果たしている。

 海馬CA1領域における長期増強長期抑圧NMDA型グルタミン酸受容体の活性化によりCa2+が流入し、カルモジュリンと結合することで下流の酵素を活性化して引き起こされる。中でも、カルモジュリンの脳内での主要なターゲットのひとつであるCaMKIIは、Ca2+濃度の低い基底状態ではカルモジュリン結合ドメインとオーバーラップしている自己抑制ドメインによってそのキナーゼ活性が低く抑えられているが、Ca2+上昇に伴ってCa2+/カルモジュリンと結合し、コンフォメーションが変化することでこの自己抑制がはずれ、活性化する[74]。また、CaMKIIは12量体を作っており[75][76]、活性化に伴って隣接するキナーゼサブユニットの間で286番目のスレオニンリン酸化することで、Ca2+/カルモジュリンとの親和性が高くなるとともに[77]、Ca2+/カルモジュリンが解離した後も部分的な活性を持続する"Autonomous"な状態を保持することができる[78][79]。CaMKIIは海馬のシェーファー側枝からCA1錐体細胞への長期増強に関わることがが報告されており[80][81][82]、CaMKIIαのノックアウトマウス点変異導入マウスでは海馬依存的な空間学習に異常がみられる[83][84]。    同様にカルモジュリンによって活性化されるアデニル酸シクラーゼ18やカルシニューリンもシナプス可塑性や記憶・学習に関与することが薬理学的実験や遺伝子改変動物実験などによって報告されている[85][86][87][88]

 こうした電気生理学的・行動学的な変化を引き起こす分子・細胞生物学的なプロセスとして、カルモジュリンはCa2+流入に伴うスパイン構造的可塑性の誘導[89][90][91]アクチン細胞骨格の再構築[92][93]、種々の酵素の活性化[94][95][96]CREBを介した新規遺伝子発現[97][98][99]に関わることが示されている。また、数あるカルモジュリン依存的な酵素の活性化は均等に起こるのではなく、Ca2+流入に伴うカルモジュリン依存的な酵素の活性化は均等に起こるのではなく、神経入力のパターンに応じて上昇したCa2+の時間的・空間的拡がりに応じて異なる強弱で活性化され、状況に応じて適切な神経細胞機能を発現していると考えられている[100][101]

阻害剤

 1974年にWeissらが、カルモジュリンにより活性化される脳のホスホジエステラーゼに対するフェノチアジン誘導体の阻害効果の作用機序およびキネティクスを報告し、カルモジュリン阻害剤であることを示した[102](これに先立つ1968年、Hondaらはフェノチアジン誘導体の環状ヌクレオチドホスホジエステラーゼに対する阻害効果が脳由来の酵素と心臓由来の酵素で異なることを報告している[103])。この後、W-7[104]カルミダゾリウム[105]など、さまざまな物質がカルモジュリン阻害剤として働くことが見出されている[106][107]

疾患と関連するカルモジュリンの変異

 カルモジュリンの点突然変異が、カテコールアミン誘発性多形性心室性頻拍QT延長症候群、特発性心室細動で見出されている(表3)。

表3. 疾患と関連するカルモジュリンの変異
疾患名 遺伝子名 変異 文献
カテコールアミン誘発性多形性心室性頻拍 (CPVT) CALM1 N53I [108]
N97S [108]
QT延長症候群 (LQTS) CALM1 D129G [109]
F141L [109]
CALM2 D95V [110]
N97S [110]
N97I [109]
D133H [110]
CLAM3 D129G [111]
CPVT・LQTSの合併 CALM2 D131E [110]
Q135P [110]
特発性心室細動(IVF) CALM1 F89L [112]

 また、癌ゲノム解析により、多数の体細胞変異が見つかっているが、その機能については良く分かっていない[113][114][115]

カルモジュリンを用いたCa2+インディケーター

 カルモジュリンがCa2+依存的にターゲットペプチドと相互作用することを用いて、様々なGenetically-encoded Ca2+ indicatorが開発されている。大まかには、2色の異なる色の蛍光タンパク質間の蛍光共鳴エネルギー移動を用いてその2色の蛍光強度の比をレシオメトリック測定することが可能なFRETセンサー(Cameleonなど)と[116][117]円順列変異GFPを用いてその蛍光強度からCa2+濃度を測定する緑色蛍光プローブ(G-CaMPなど)がある[118][119]Cameleonの場合、Ca2+と結合したカルモジュリンがそのターゲットのM13ペプチドと結合することでコンフォメーションが変化し、2色の蛍光タンパク質の間での蛍光共鳴エネルギー移動の効率が変わることを利用している。一方で、G-CaMPの場合には、カルモジュリンとM13ペプチドの結合によるコンフォメーション変化が発色団周囲の環境を変化させることにより、蛍光強度が変化することを利用している。

 2000年代以降、これらの改良が進んでおり、変化率を大きくしたものや単一活動電位を記録できる高感度のもの、キネティクスが速いもの、さまざまな色のインディケーターなどが開発され、生きた動物個体の中での神経細胞やシナプスの活動を長期間観察するのに用いられている[120][121][122][123][124][125][126][127][128][129]

関連項目

参考文献

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    Structure of calmodulin refined at 2.2 A resolution.
    J. Mol. Biol.: 1988, 204(1);191-204 [PubMed:3145979] [WorldCat.org]

  2. 2.0 2.1 S Kakiuchi, R Yamazaki
    Stimulation of the activity of cyclic 3',5'-nucleotide phosphodiesterase by calcium ion.
    Proc. Japan Acad. 46, 387-392:1970
  3. S Kakiuchi, R Yamazaki, H Nakajima
    Properties of a heat-stable phosphodiesterase activating factor isolated from brain extract
    Proc. Japan Acad. 46, 587-592:1970
  4. S Kakiuchi, R Yamazaki

    Calcium dependent phosphodiesterase activity and its activating factor (PAF) from brain studies on cyclic 3',5'-nucleotide phosphodiesterase (3).
    Biochem. Biophys. Res. Commun.: 1970, 41(5);1104-10 [PubMed:4320714] [WorldCat.org]

  5. W Y Cheung

    Cyclic 3',5'-nucleotide phosphodiesterase. Demonstration of an activator.
    Biochem. Biophys. Res. Commun.: 1970, 38(3);533-8 [PubMed:4315350] [WorldCat.org]

  6. T S Teo, T H Wang, J H Wang

    Purification and properties of the protein activator of bovine heart cyclic adenosine 3',5'-monophosphate phosphodiesterase.
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  7. T S Teo, J H Wang

    Mechanism of activation of a cyclic adenosine 3':5'-monophosphate phosphodiesterase from bovine heart by calcium ions. Identification of the protein activator as a Ca2+ binding protein.
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  8. 日高弘義、垣内史朗 編
    カルモデュリン―Ca2+受容蛋白質
    1981
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    An endogenous Ca2+-dependent activator protein of brain adenylate cyclase and cyclic neucleotide phosphodiesterase.
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    Three-dimensional structure of calmodulin.
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  18. M W Berchtold, R Egli, J A Rhyner, H Hameister, E E Strehler

    Localization of the human bona fide calmodulin genes CALM1, CALM2, and CALM3 to chromosomes 14q24-q31, 2p21.1-p21.3, and 19q13.2-q13.3.
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  19. Zhengui Xia, Daniel R Storm

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  22. Henning Tidow, Poul Nissen

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    Calmodulin and STIM proteins: Two major calcium sensors in the cytoplasm and endoplasmic reticulum.
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