人类PAPP-A2的冷EM结构和基质识别机制
Janani Sridar1, Amirhossein Mafi1, Russell A Judge2
1Calico Life Sciences LLC, South San Francisco, CA, 94080, USA.
Communications chemistry
|October 29, 2023
概括
与怀孕相关的血蛋白A2 (PAPP-A2) 结构揭示了它如何分裂IGFBP5.5. 在M2域中的差异解释了PAPP-A2的存在.
科学领域:
- 生物化学和结构生物学
- 分子和细胞生物学 分子和细胞生物学
背景情况:
- 妊娠相关血蛋白A (PAPP-A) 和PAPP-A2是金属蛋白酶,通过分裂IGF结合蛋白 (IGFBPs) 来调节类似胰岛素的生长因子 (IGF) 信号传递.
- 之前的研究报告了同质PAPP-A的结构,但缺乏单质PAPP-A2.2的结构数据.
研究的目的:
- 确定单体人类PAPP-A2的冷EM结构,重点关注其N端域.
- 为了研究影响PAPP-A2活动的患者突变的功能影响.
- 阐明IGFBP5被PAPP-A2分裂的机制,并将其与PAPP-A进行比较.
主要方法:
- 单粒子冷电子显微镜 (cryo-EM) 用于在3.13 Å分辨率下确定人类PAPP-A2的结构.
- 功能性测试研究IGFBP5裂变和患者突变的影响.
- 与现有的PAPP-A结构和功能数据进行比较分析.
主要成果:
- 该研究介绍了单体PAPP-A2的冷-EM结构,包括其N端LG,MP和M1域.
- 结构和功能数据提供了一个突变的洞察力,该突变使PAPP-A2.2失活.
- PAPP-A2与PAPP-A类似地识别IGFBP5,但由于M2域差异,其裂变效率较低.
结论:
- 描述的结构和功能研究阐明了IGFBP5通过PAPP-A2.2的裂变机制.
- 在M2域中,PAPP-A2和PAPP-A之间的关键结构差异影响IGFBP5裂变效率.
- 这项工作提高了PAPP-A家族成员对IGF信号调节的理解.
相关概念视频
Cryo-electron Microscopy
3.3K
Conventional electron microscopy (EM) involves dehydration, fixation, and staining of biological samples, which distorts the native state of biological molecules and results in several artifacts. Also, the high-energy electron beam damages the sample and makes it difficult to obtain high-resolution images. These issues can be addressed using cryo-EM, which uses frozen samples and gentler electron beams. The technique was developed by Jacques Dubochet, Joachim Frank, and Richard Henderson, for...
3.3K
Molecular Chaperones and Protein Folding
18.0K
The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
The...
18.0K
Allosteric Proteins-ATCase
5.8K
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...
5.8K
ATP Synthase: Structure
12.5K
ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
12.5K


