Characterising molecular details of protein (mis)folding mechanisms during biosynthesis, towards developing a disease-modifying toolkit

Lisa Cabrita (primary)
Structural and Molecular Biology
University College London
John Christodoulou (secondary)
Structural and Molecular Biology
University College London

Abstract

Successful protein folding and structure formation is essential for maintaining cellular homeostasis. Protein folding, however, competes directly with potentially devastating misfolding, which can lead to a range of human conformational diseases. Protein biosynthesis as it occurs on the ribosome is the first place where the emerging nascent polypeptide chain faces its first opportunity to either beginning to fold or misfold, co-translationally. This project aims to develop a novel toolkit by combining biochemistry and integrative structural biology to rescue protein misfolding as it occurs within the cell by exploiting the unique structural and dynamic features of newly synthesising polypeptide chains.


References

Cabrita LD*, Cassaignau AME* et al. A structural ensemble of a ribosome-nascent chain complex during cotranslational protein folding. Nat Struct Mol Biol. 2016;23(4):278-285. doi: 10.1038/nsmb.3182

Deckert A et al. Structural characterisation of the interaction of α-synuclein nascent chains with the ribosomal surface and trigger factor. Proc Natl Acad Sci U S A. 2016;113(18):5012-7. doi: 10.1073/pnas.1519124113

Waudby CA et al. Systematic mapping of free energy landscapes of a growing filamin domain during biosynthesis. Proc Natl Acad Sci U S A. 2018;115(39):9744-9749. doi: 10.1073/pnas.1716252115

Plessa E*, Chu LP* et al, Cotranslational protein misfolding and aggregation can begin on the ribosome (Manuscript available upon request).


BBSRC Area
Molecules, cells and industrial biotechnology
Area of Biology
BiotechnologyStructural Biology
Techniques & Approaches
BiochemistryBiophysicsMathematics / StatisticsMolecular BiologySimulation / Modelling