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Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

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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...
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Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

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The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

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Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
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Phosphorylation01:02

Phosphorylation

53.6K
The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
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Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

8.7K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
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Updated: Jan 15, 2026

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

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ホスファターゼSHP2の病原性変異は、構造サンプリングを変化させることで活性を高める

Andrew W Glaser1, Ricardo A P Pádua1,2, Adedolapo M Ojoawo1,2

  • 1Department of Biochemistry and Biophysics, Brandeis University and HHMI, Waltham, MA 02453.

Proceedings of the National Academy of Sciences of the United States of America
|January 13, 2026
PubMed
まとめ
この要約は機械生成です。

SHP2タンパク質チロシンホスファターゼのT42A変異は、ジップコンフォメーションを安定化させることにより、ホスホペプチド結合を強化する。この研究は、細胞シグナル伝達のためのSHP2調節と調節不全の原子メカニズムを明らかにする。

キーワード:
NMRSH2SHP2アロステリーダイナミクス

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Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases
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Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases

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Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes
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Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes

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関連する実験動画

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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases
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科学分野:

  • 分子生物学
  • 構造生物学
  • 生化学

背景:

  • SH2ドメインは、ホスホペプチド配位子を結合することにより細胞シグナル伝達を媒介します。
  • SHP2は細胞シグナル伝達の重要な調節因子であり、その調節不全は疾患に関与しています。
  • SH2ドメイン結合およびSHP2活性化の正確なメカニズムは完全には理解されていません。

研究 の 目的:

  • SHP2の調節および調節不全の原子メカニズムを調査すること。
  • SHP2におけるE139DおよびT42A変異の論争的なメカニズムを解明すること。
  • 主要な水素結合を破壊しているにもかかわらず、T42A変異が結合親和性を増加させるというパラドックスを解決すること。

主な方法:

  • X線アンサンブルリファインメント
  • NMR緩和研究
  • 計算モデリング

主要な成果:

  • T42A変異はN-SH2ドメインを安定化されたジップ型βシート構造へとシフトさせます。
  • この構造シフトはミリ秒オーダーのコンフォメーション交換を抑制し、ホスホペプチド結合親和性を高めます。
  • これらの発見は、T42A誘発性過剰活性化の構造的基盤を提供し、SHP2活性化に関する相反するモデルを調和させます。

結論:

  • 相補的な構造的および動的アプローチにより、SHP2調節メカニズムが明らかになります。
  • 本研究は、SH2媒介性ホスホペプチド認識に関する洞察を提供します。
  • これらのメカニズムを理解することは、SHP2関連疾患の治療戦略に役立つ可能性があります。