用ADAM10进行基质膜近接蛋白解的结构基础
Colin H Lipper1, Emily D Egan1, Khal-Hentz Gabriel2
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Cell
|July 29, 2023
概括
ADAM10蛋白的活性由四氨酸Tspan15调节,它将其活性部位定位为膜附近的裂. 这种机制对于哺乳动物的发育和APP处理至关重要,提供疾病调节策略.
科学领域:
- 生物化学
- 结构生物学
- 细胞生物学
背景情况:
- ADAM10是一种必要的内酶,可催化受调节的蛋白质分解和非粉原性APP裂变.
- ADAM10的功能取决于与四氨酸蛋白的复合形成,但膜裂变的活性位点定位的机制尚不清楚.
研究的目的:
- 阐明四氨酸结合使ADAM10膜-近位基质裂变的结构机制.
- 调查四氨酸相互作用如何影响ADAM10基质的特异性和裂变部位的选择.
主要方法:
- 用冷电子显微镜 (cryo-EM) 确定vFab-ADAM10-Tspan15复合物的结构.
- 基于细胞的测试以评估N-cadherin脱落和ADAM10活性.
主要成果:
- 化EM结构显示Tspan15的结合缓解了ADAM10的自身抑制.
- Tspan15 作为一个分子统治器,将ADAM10 活性位点定位在离血大约 20 Å 的距离之内.
- 正如N-cadherin分泌试验所示,ADAM10-Tspan15接口会影响裂变部位的选择.
结论:
- 在膜附近的ADAM10蛋白质分解中,四氨酸的结合至关重要.
- 这些结构见解为ADAM10介导的裂变提供了一种机制,并为涉及ADAM10失调的疾病的治疗调节提供了基础.
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