A cryo-electron microscopic approach to elucidate protein structures from human brain microsomes

We recently developed a Build and Retrieve cryo-electron microscopy (cryo-EM) methodology, which is capable of simultaneously producing near-atomic resolution cryo-EM maps for several individual proteins from a heterogeneous, multiprotein sample. Here we report the use of Build and Retrieve to define the composition of a raw human brain microsomal lysate. From this sample, we simultaneously identify and solve cryo-EM structures of five different brain enzymes whose functions affect neurotransmitter recycling, iron metabolism, glycolysis, axonal development, energy homeostasis, and retinoic acid biosynthesis. Interestingly, malfunction of these important proteins has been directly linked to several neurodegenerative disorders, such as Alzheimer's, Huntington's, and Parkinson's diseases. Our work underscores the importance of cryo-EM in facilitating tissue and organ proteomics at the atomic level.

Automated summary

We have developed a new cryo-EM method that can simultaneously determine the atomic resolution structures of multiple proteins. Using this method, we have identified the composition of a human brain microsomal lysate and solved the structures of five proteins related to neurodegenerative diseases. This highlights the importance of cryo-EM in facilitating tissue and organ proteomics at the atomic level.