自閉症に関連した変異がUBE3Aのリン酸化制御を無効にします
Jason J Yi1, Janet Berrios2, Jason M Newbern3
1Department of Cell Biology and Physiology and UNC Neuroscience Center, The University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, The University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina, Chapel Hill, NC 27599, USA.
Cell
|August 11, 2015
まとめ
タンパク質キナーゼA (PKA) は,脳発達の重要な遺伝子であるUBE3Aを調節する. 自閉症に関連した変異は,この調節を妨害し,過剰なUBE3A活動と潜在的なシナプス機能不全を引き起こす.
科学分野:
- 神経科学
- 遺伝学
- 生物化学
背景:
- UBE3Aの削除はエンジェルマン症候群 (AS) を引き起こし,その重複/三重化は自閉症に関連しています.
- UBE3Aユビキチンリガースの適切な調節は,正常な脳の発達に不可欠です.
研究 の 目的:
- UBE3A活動のアップストリーム規制を調査する.
- UBE3Aのリン酸化と活性に対する自閉症関連変異の機能的影響を決定する.
主な方法:
- PKAによるUBE3Aのリン酸化を評価するためのインビトロキナーゼアッセイ
- UBE3Aとその基質を用いた酵素活性測定法
- 患者の細胞と脳組織を分析し,UBE3Aの活性と脊髄の樹状形状を評価する.
主要な成果:
- タンパク質キナーゼA (PKA) は,残基T485でUBE3Aをリン酸化し,そのリガース活性を抑制する.
- T485における新たな自閉症関連変異は,PKA媒介の抑制を妨害し,UBE3Aの活性化につながります.
- 強化されたUBE3A活性により,基板の周回が増加し,脳組織における多角脊椎の発達が増加します.
結論:
- PKAはUBE3Aのアップストリームレギュレータであり,T485でのリン酸化によってその活動を制御する.
- このリン酸化部位が自閉症に関連した変異によって破壊されると,過剰なUBE3A活性が生じます.
- 過剰なUBE3A活動と,その後のシナプス機能障害は,自閉症の病原性に関連しています.
関連する概念動画
02:04Covalently Linked Protein Regulators
9.9K
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....
These groups modify specific amino acids in a protein....
9.9K
01:19Allosteric Proteins-ATCase
6.9K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
6.9K
01:13The Proteasome
2.0K
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
2.0K
02:18The Proteasome
10.6K
Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
10.6K
02:23Abnormal Proliferation
5.4K
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...
5.4K
01:37The Unfolded Protein Response
7.0K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
7.0K