Portrait of a Protein

The structure of Transcription factor II Human, as revealed by cryo-electron microscopy. Each color represents a different protein molecule.

Basil Greber and Eva Nogales, UC Berkeley/Lawrence Berkeley National Laboratory

Proteins epitomize the axiom “form follows function.” The unique shape of a protein determines how it precisely slots into other molecules, like a three-dimensional jigsaw puzzle piece. Because even slight structural malformations can lead to dysfunction and disease, researchers are making every effort to deduce the architecture of key proteins. A new study has reported a breakthrough in visualizing a particularly complex protein known as Transcription factor II Human (TFIIH) at near-atomic resolution. 

TFIIH separates the rung-like strands within DNA so that genes can be accessed, both for repair and for carrying out the routine business of life. Scientists have long investigated TFIIH due to its roles in cancers, premature aging, and several genetic diseases, but traditional imaging methods have failed to accurately characterize the protein. A team of researchers led by Eva Nogales, a faculty scientist in the Molecular Biophysics and Integrated Bioimaging Division at Lawrence Berkeley National Laboratory in California, used a combination of cryo-electron microscopy and supercomputing to succeed where others have failed. 

Cryo-electron microscopy, or cryo-EM, involves flash-freezing samples so quickly that structure-damaging ice crystals do not have time to form. Electrons are then pumped in, generating light that is detected by cameras. The technique can achieve image resolution down to the level of nearly individual atoms, ultimately delivering highly accurate maps of proteins. Although the infusion of electrons can trigger movement in the sample and blur its appearance, the Berkeley team worked around this issue by creating movies of each imaged sample of TFIIH, snapping multiple shots from different angles. All the generated data—1.5 million images in all—were then sifted by a supercomputer and further processed to glean TFIIH’s true shape. 

With this layout of the protein in hand, researchers can now explore how TFIIH performs its functions when properly constructed. Further efforts will focus on creating drugs tailored to fixing the protein when mutations have thrown off its delicate design. According to Nogales, who is also a University of California, Berkeley professor of molecular and cell biology and a Howard Hughes Medical Institute investigator, “Cryo-EM will enable great progress, both for our understanding of the basic principles of the molecular functioning of the cell, and for applications, such as structure-based drug design.” Other scientists also agree on the power and promise of cryo-EM; its developers were awarded the 2017 Nobel Prize for Chemistry. (Nature