Rasスーパーファミリーの小型GTPasesの形態学分類に基づく機能スイッチング変異体
1Department of Molecular Pharmacology, Stanford University School of Medicine, 269 Campus Drive, Room 3215, Stanford, CA 94305, USA.
Cell
|May 7, 2003
まとめ
研究者らは,細胞機能を切り替えるためにタンパク質にシグナルを送る重要なアミノ酸の位置を特定した. この発見は,タンパク質ファミリーを理解し,標的型療法を開発するのに役立ちます.
科学分野:
- 細胞生物学 細胞生物学
- 分子生物学は分子生物学である.
- タンパク質シグナル伝達
背景:
- 同じファミリー内のシグナル伝達タンパク質は,多様な細胞機能を示すことができます.
- この機能的特異性の決定因子を理解することは,分子生物学と疾患研究において極めて重要です.
研究 の 目的:
- 小型GTPasesの機能を切り替える特定のアミノ酸残基を特定する.
- スイッチ・オブ・ファンクション・ミュータントを作成するための予測アルゴリズムを開発する.
主な方法:
- 細胞形態を異なるグループに分類するために100の構成的に活性なヒト小GTPasesの発現.
- 機能的なスイッチングのためのアミノ酸の位置を特定するための予測アルゴリズムの開発.
- いくつかの小さなGTPasesのスイッチ・オブ・ファンクションミュータントを作成することによって,アルゴリズムの実験的検証.
主要な成果:
- 小型GTPasesの発現は,9つの異なる細胞形態学クラスをもたらしました.
- 開発されたアルゴリズムは,機能的なスイッチングのためのアミノ酸の位置をうまく予測しました.
- Rac1,CDC42,H-Ras,RalA,Rap2B,R-Ras3.3のために有効な機能スイッチング変異体が作成されました.
- 機能的なスイッチングの鍵となる残留物は,しばしば既知の相互作用表面の外にあり,構造的に分散していた.
結論:
- ゲノム全体の機能的分類とスイッチ・オブ・ファンクション・ミュータント・ジェネレーションの組み合わせは,タンパク質ファミリー特異性を探求する強力なアプローチです.
- この発見は,タンパク質の機能と特異性を支配する残留物の位置に関する既存の概念に異議を唱えている.
関連する概念動画
GTPases and their Regulation
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
Large G-proteins, also known...
The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...
GTPases and their Regulation
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
Large G-proteins, also known...
Rab Cascades
Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
Small GTPases - Ras and Rho
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...


