Paula da Fonseca

MRC-Laboratory of Molecular Biology

Paula da Fonseca is a Group Leader in the LMB’s Structural Studies Division. 

Paula da Fonseca first ran across the proteasome, the cell’s protein recycling centre, during her pre-doctoral fellowship in Portugal, but it wasn’t until she saw it by electron microscopy as a postdoc at Imperial College that she truly fell in love with it, as she had with electron microscopy during her PhD. “Actually seeing a protein complex for the first time was a very special moment”, she says. “I knew from the outset it was what I wanted to do.”

The proteasome is a big multi-subunit complex that’s absolutely required for the smooth running of a cell. Without it, proteins aren’t degraded properly, and the resulting garbage build-up is incredibly damaging; indeed, proteasome inhibitors are potent chemotherapy agents. At the heart of the proteasome lies the catalytic subunit, a barrel-shaped structure that acts like a tiny wood-chipper, shredding proteins fed into it by the regulatory subunits, which cap the barrel at both ends, and carry highly sophisticated mechanisms for detecting and trapping elderly or defective proteins, or proteins that need to be removed for the cell to progress to the next phase of division.

The architecture of the regulatory cap was mostly unknown when Paula started her postdoc at Imperial, and it took until 2012, and a move to the Institute of Cancer Research, before she, Jun He and Ed Morris were able to publish a molecular model of the whole human proteasome, derived from electron cryo-microscopy (cryo-EM) images, a tour de force that finally allowed a mechanistic understanding of the complex.

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