PTEN腫瘍抑制剤の結晶構造:そのフォスホイノシチド・フォスファタゼ活性と膜関連性への影響
J O Lee1, H Yang, M M Georgescu
1Cellular Biochemistry and Biophysics Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cell
|November 11, 1999
まとめ
がんにおいて重要なPTEN腫瘍抑制タンパク質は,フォスファターゼとして作用する. その構造は,それがどのように膜を結合し,その腫瘍抑制機能を助けるかを明らかにします.
科学分野:
- バイオケミストリー バイオケミストリー
- 分子生物学は分子生物学である.
- がん研究 がん研究
背景:
- PTENは,ヒトの癌で頻繁に変異する重要な腫瘍抑制剤です.
- PTENは,タンパク質と脂質の両方の基板に作用するフォスファターゼとして機能します.
研究 の 目的:
- PTENの基板特異性と膜相互作用の構造的基礎を解明する.
- PTENのC2ドメインが,その触媒活性と腫瘍抑制にどのように影響するかを理解する.
主な方法:
- PTENの3次元構造を決定するX線結晶学.
- PTENのフォスファタゼ活性と膜結合を評価するための生化学的測定法.
- サイト・ディレクテッド・ミュータゲネシスで,C2ドメインの機能における特定の残留物の役割を調査する.
主要な成果:
- PTEN構造は,フォスホイノシチド結合のための拡大された活性部位とC2ドメインを持つフォスファタゼドメインを明らかにします.
- C2ドメインは直接フォスフォリピド膜に結合し,この結合を阻害する変異はPTENの膜親和性を減少させます.
- PTENのフォスファタゼとC2ドメインは広く相互作用し,C2ドメインが触媒ドメインを膜に配置することを示唆しています.
結論:
- C2ドメインは,PTENの膜局所化と腫瘍抑制活動に不可欠です.
- PTENの構造は,がんにおける脂質フォスファタゼとしての作用機構の洞察を提供します.
- PTEN-膜相互作用をターゲットにすることで,PTEN欠乏がんに対する新しい治療戦略を提供することができる.
関連する概念動画
02:54Protein Kinases and Phosphatases
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:42Phosphoinositides and PIPs
Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
01:19Interactions Between Signaling Pathways
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:22PI3K/mTOR/AKT Signaling Pathway
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a rapamycin-insensitive companion...
01:23Catenins
Catenins are characterized by multiple binding domains and dynamic structures that allow them to function as linker proteins in cell junction complexes. All catenins, except α-catenin, contain a characteristic protein sequence called the armadillo repeat and are therefore also called armadillo proteins.
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the adherens...
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the adherens...