CaM

カルモジュリン

WordNet

1. the 3rd letter of the Roman alphabet (同)c
2. (music) the keynote of the scale of C major
3. a general-purpose programing language closely associated with the UNIX operating system
4. a rotating disk shaped to convert circular into linear motion

PrepTutorEJDIC

1. carbonの化学記号
2. カム,歪(わい)輪(機械の回転運動を水平・上下などの運動に変える)
3. Calciumの化学記号

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/02/07 16:55:44」(JST)

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カルモジュリンの立体構造

カルモジュリン（英: Calmodulin、CaM）は、至る所にあるカルシウム結合タンパク質で、多くの種類のタンパク質を対象として制御を行うため、様々な細胞機能に影響を与え、炎症、代謝、アポトーシス、筋肉収縮、細胞内移動、短期記憶、長期記憶、神経成長、免疫反応などさまざまな過程とかかわっている。

カルモジュリンは様々な型の細胞で発現しており、細胞内の存在箇所も、細胞内小器官内、膜の上なども含め様々である。 タンパク質の多くは単独ではカルシウムに結合することはできず、カルモジュリンを利用してカルシウム検出や信号変換を行う。 カルモジュリンは小胞体や筋小胞体にカルシウムの貯蔵も行う。 カルモジュリンはカルシウムが結合すると構造変化を引き起こし、特定の反応のための特定のタンパク質に結合できるようになる。

結合できるカルシウムは1分子当たり4つで、リン酸化、アセチル化、メチル化、タンパク質切断などの翻訳後修飾を受けることがある。

カルモジュリンは小さい酸性のタンパク質で、約148残基のアミノ酸から構成されている。分子量は16706ダルトンで、よくタンパク質シミュレーションソフトで利用される。4つのEFハンドモチーフ（ドメイン）を持っており、それぞれにCa²⁺イオンが結合する。

カルモジュリンは炭疽菌が分泌する炭疽毒にも結合することで知られる。

外部リンク

RCSB PDB-101 Calmodulin

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Calmodulin 3D structure

The helix loop helix structure of the calcium binding EF hand motif

Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca²⁺, and the binding of Ca²⁺ is required for the activation of Calmodulin. Once bound to Ca²⁺, Calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases.

Structure

Calmodulin is a small, highly conserved protein that is 148 amino acids long (16.7 KDa). The protein has two approximately symmetrical globular domains each containing a pair of EF-hand motifs (the N- and C-domain) separated by a flexible linker region for a total of four Ca²⁺ binding sites. Each EF-hand motif allows calmodulin to sense intracellular calcium levels by binding one Ca²⁺ ion. Calcium ion binding regions are found in the following positions in the sequence of amino acids: 21-32, 57-68, 94-105 and 130-141; each region that calcium binds to is exactly 12 amino acids long. These regions are located between two alpha helices in the EF-hand motifs, the first two regions (21-32 and 57-68) are on one side of the linker region the other two (94-105 and 130-141) are on the other side.

Importance of Flexibility in Calmodulin

Calmodulin binds such a wide variety of target proteins, making it especially important for it to have flexibility. Though Calmodulin's flexibility is more evident when it is bound to a target protein, NMR studies have shown that the linker region of Calmodulin is flexible, even when it is not bound to a target protein. Another important characteristic of calmodulin that allows it to bind a large variety of target proteins is the generic shape of the non-polar grooves in the binding sites. Since the non-polar grooves are generic, they don't require the target proteins to have any specific sequence of amino acids allowing a larger variety of target proteins to be bound. Together, these two structural characteristics of calmodulin allow it to flexibly bind target proteins with various shapes and amino acid sequences. For example, calmodulin binds both NMDA receptors and potassium channels which differ in length by about 50 amino acid residues.

On the left: Calmodulin with four calcium ions bound. On the right: Troponin C with four calcium ions bound.

Similarity to Troponin C

Calmodulin's structure is very similar to the structure of Troponin C (which is another calcium binding protein). They are both members of the EFh superfamily. Troponin C, like Calmodulin, has two globular domains that are connected by a linker region. However, Troponin C and Calmodulin differ in the length of the linker region; the linker region of Calmodulin is smaller than that of Troponin C. These remarkably similar structures are an example of how the EF hand motif is highly conserved in calcium binding proteins. Though they have similar structures, their functions are very different. Troponin C has a very specific function (to elicit a conformational change in Troponin I) ultimately causing a contraction in skeletal muscles. Calmodulin, evolved to bind a wider variety of target proteins, allowing it to play a role in many physiological events.

Mechanism

This images shows conformational changes in calmodulin. On the left is calmodulin without calcium and on the right is calmodulin with calcium. Sites that bind target proteins are indicated by red stars.

Overall

Solution structure of Calcium calmodulin C-terminal domain

Solution structure of Calcium-calmodulin N-terminal domain

Up to four calcium ions are bound by calmodulin via its four EF hand motifs. EF hands supply an electronegative environment for ion coordination. After calcium binding, hydrophobic methyl groups from methionine residues become exposed on the protein via conformational change. Using both X-Ray and NMR studies, scientists were able to determine that the conformational changes occurred in the alpha-helices of the EF motif, which changes the binding affinity for target proteins. When the alpha helices are perpendicular to one another, the Calmodulin is in an open conformation giving it a higher affinity for target proteins. More specifically, this conformational change presents hydrophobic surfaces, which can in turn bind to Basic Amphiphilic Helices (BAA helices) on the target protein. These helices contain complementary hydrophobic regions. The flexibility of calmodulin's hinged region allows the molecule to wrap around its target. This property allows it to tightly bind to a wide range of different target proteins. The C-domain of calmodulin has a higher affinity for calcium than does the N-domain.

Dynamic features

The C-terminal domain solution structure is similar to the X-ray crystal structure, while the EF hands of the N-terminal domain are considerably less open to the X-ray crystal structure. This indicates that Ca²⁺ binding causes a larger conformational change in the N-domain than in the C-domain. The backbone flexibility within calmodulin is key to its ability to bind a wide range of targets. Protein domains, connected by intrinsically disordered flexible linker domains, induce long-range allostery, or the conformational change of a protein by ligand binding to an allosteric site (a site other than the functional site), via protein domain dynamics.

Function

General role in the body

Calmodulin mediates many crucial processes such as inflammation, metabolism, apoptosis, smooth muscle contraction, intracellular movement, short-term and long-term memory, and the immune response. Calcium participates in an intracellular signaling system by acting as a diffusible second messenger to the initial stimuli. It does this by binding various targets in the cell including a large number of enzymes, ion channels, aquaporins and other proteins. Calmodulin is expressed in many cell types and can have different subcellular locations, including the cytoplasm, within organelles, or associated with the plasma or organelle membranes, but it is always found intracellularly. Many of the proteins that Calmodulin binds are unable to bind calcium themselves, and use calmodulin as a calcium sensor and signal transducer. Calmodulin can also make use of the calcium stores in the endoplasmic reticulum, and the sarcoplasmic reticulum. Calmodulin can undergo post-translational modifications, such as phosphorylation, acetylation, methylation and proteolytic cleavage, each of which has potential to modulate its actions.

Specific Examples

Role in smooth muscle contraction

Calmodulin bound to MLC Kinase (from PDB).

Calmodulin plays an important role in excitation contraction (EC) coupling and the initiation of the cross-bridge cycling in smooth muscle, ultimately causing smooth muscle contraction. In order to activate contraction of smooth muscle, the head of the myosin light chain must be phosphorylated. This phosphorylation is done by Myosin Light Chain (MLC) Kinase. This MLC Kinase is activated by a calmodulin when it is bound by calcium, thus making smooth muscle contraction dependent on the presence of calcium, through the binding of calmodulin and activation of MLC kinase.

Another way that calmodulin affects muscle contraction is by controlling the movement of Ca²⁺ across both the cell and sarcoplasmic reticulum membranes. The Ca²⁺ channels, such as the ryanodine receptor of the sarcoplasmic reticulum, can be inhibited by calmodulin bound to calcium, thus affecting the overall levels of calcium in the cell.

This is a very important function of calmodulin because it indirectly plays a role in every physiological process that is affected by smooth muscle contraction such as digestion and contraction of arteries (which helps distribute blood and regulate blood pressure).

Role in metabolism

Calmodulin plays an important role in the activation of phosphorylase kinase, which ultimately leads to glucose being cleaved from glycogen by glycogen phosphorylase.

Calmodulin also plays an important role in lipid metabolism by affecting Calcitonin. Calcitonin is a polypeptide hormone that lowers blood Ca²⁺ levels and activates G Protein cascades that leads to the generation of cAMP. The actions of calcitonin can be blocked by inhibiting the actions of calmodulin, suggesting that calmodulin plays a crucial role in the activation of calcitonin.

Role in short-term and long-term memory

Long-term potentiation (LTP) requires a depolarization of GABAergic neurons (Neurons that use GABA as a neurotransmitter) in the hippocampus. Calmodulin Kinase II (CaM-K II) plays a crucial role in achieving LTP. It contributes to the phosphorylation of an AMPA receptor which increases the sensitivity of AMPA receptors. Furthermore, research shows that inhibiting CaM-K II interferes with LTP.

Family members

• Calmodulin 1 (CALM1)
• Calmodulin 2 (CALM2)
• Calmodulin 3 (CALM3)
• Calmodulin-like 1 (CALML1)
• Calmodulin-like 3 (CALML3)
• Calmodulin-like 4 (CALML4)
• Calmodulin-like 5 (CALML5)
• Calmodulin-like 6 (CALML6)

Other calcium-binding proteins

Calmodulin belongs to one of the two main groups of calcium-binding proteins, called EF hand proteins. The other group, called annexins, bind calcium and phospholipid (e.g., lipocortin). Many other proteins bind calcium, although binding calcium may not be considered their principal function in the cell.

See also

• Proteopedia page for Calmodulin and its conformational change
• Protein kinase
• Ca2+/calmodulin-dependent protein kinase

References

External links

• RCSB details...
• Calmodulin at the US National Library of Medicine Medical Subject Headings (MeSH)
• InterPro: IPR015754
• Jennifer McDowall (2003-01-01). "Calmodulin". InterPro Protein Archive. Retrieved 2008-03-22. 
• Melanie Nelson; Walter Chazin. "Home Page for Calmodulin". EF-Hand Calcium-Binding Proteins Data Library. Vanderbilt University. Retrieved 2008-03-22. 
• Mitsuhiko Ikura. "Calmodulin Target Database". Ontario Cancer Institute, University of Toronto. Retrieved 2008-03-22. 

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Related Pictures

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★リンクテーブル★

リンク元	「カルモジュリン」「calmodulin」
拡張検索	「CaM kinase II」「CaMキナーゼI」「CaMV」「CaM結合ドメイン」「CaM-kinase」
関連記事	「C」「CAM」「Ca」

「カルモジュリン」

　　[★]

英

calmodulin, CaM

関

カルシウム

「calmodulin」

　　[★] カルモジュリン CaM

「CaM kinase II」

　　[★]

• カルモジュリンキナーゼII、カルモジュリン依存性キナーゼII、カルモジュリン依存性プロテインキナーゼII、CaMキナーゼII

関

calcium-calmodulin-dependent protein kinase type 2、calmodulin kinase II、calmodulin-dependent protein kinase II、CaM KII、CaMKII

「CaMキナーゼI」

　　[★]

英

(n

• CaM kinase I

関

カルモジュリンキナーゼI、カルモジュリン依存性キナーゼI、カルモジュリン依存性プロテインキナーゼI

「CaMV」

　　[★] カリフラワーモザイクウイルス

「CaM結合ドメイン」

　　[★] カルモジュリン結合ドメイン

「CaM-kinase」

　　[★] カルモジュリンキナーゼ

「C」

　　[★]

• 炭素 carbon
• シトシン cytosine
• システイン cysteine
• シチジン
• セルシウス度 摂氏 degrees Celsius degree C
• 産婦人科領域で「子宮外頚 子宮外頚部 exocervix」を表現するための略語

　 　 　 　

「CAM」

　　[★]

• 絨毛膜羊膜炎 chorioamnionitis
• カルモジュリン CaM calmodulin
• CAD
• ベンケイソウ型有機酸代謝 ベンケイソウ型酸代謝 crassulacean acid metabolism
• クラリスロマイシン clarithromycin

「Ca」

　　[★] カルシウム calcium