ATP-induced asymmetric pre-protein folding as a driver of protein translocation through the Sec machinery

Author:

Corey Robin A1ORCID,Ahdash Zainab2ORCID,Shah Anokhi3,Pyle Euan24ORCID,Allen William J1ORCID,Fessl Tomas5ORCID,Lovett Janet E3ORCID,Politis Argyris2ORCID,Collinson Ian1ORCID

Affiliation:

1. School of Biochemistry, University of Bristol, Bristol, United Kingdom

2. Department of Chemistry, King's College London, London, United Kingdom

3. SUPA School of Physics and Astronomy and BSRC, University of St Andrews, Scotland, United Kingdom

4. Department of Chemistry, Imperial College London, London, United Kingdom

5. University of South Bohemia in Ceske Budejovice, České Budějovice, Czech Republic

Abstract

Transport of proteins across membranes is a fundamental process, achieved in every cell by the ‘Sec’ translocon. In prokaryotes, SecYEG associates with the motor ATPase SecA to carry out translocation for pre-protein secretion. Previously, we proposed a Brownian ratchet model for transport, whereby the free energy of ATP-turnover favours the directional diffusion of the polypeptide (Allen et al., 2016). Here, we show that ATP enhances this process by modulating secondary structure formation within the translocating protein. A combination of molecular simulation with hydrogendeuterium-exchange mass spectrometry and electron paramagnetic resonance spectroscopy reveal an asymmetry across the membrane: ATP-induced conformational changes in the cytosolic cavity promote unfolded pre-protein structure, while the exterior cavity favours its formation. This ability to exploit structure within a pre-protein is an unexplored area of protein transport, which may apply to other protein transporters, such as those of the endoplasmic reticulum and mitochondria.

Funder

Biotechnology and Biological Sciences Research Council

Wellcome

Engineering and Physical Sciences Research Council

European Regional Development Fund

Royal Society

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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