An integrative, multiscale approach to understanding the molecular basis for receptor mediated trafficking within the early secretory pathway. (360G-Wellcome-219531_Z_19_Z)

£3,027,479

The movement of proteins within eukaryotic cells is an essential process that maintains internal organelle integrity and underpins normal cell function. Despite the identification, several decades ago, of the receptors controlling protein trafficking, the molecular mechanisms of selective retention and export of ER and Golgi resident proteins still remain poorly understood. However, this recently changed when our study on the KDEL receptor revealed the structural basis by which a trafficking receptor can signal across a membrane to cytoplasmic coat protein complexes to initiate retrograde trafficking. We now aim to determine the mechanisms that underpin protein trafficking by other receptors within the early secretory pathway. We have developed an integrated approach involving cell biology and structure-based methods, including lipid-based crystallisation and single particle cryo-electron microscopy coupled with advanced protein engineering, super resolution light microscopy, and multiscale molecular dynamics analysis of trafficking complexes. Specifically, we will determine the mechanism for several cargo-receptor systems that control anterograde and retrograde protein sorting and address how sorting receptors recognise cargo proteins, and the mechanism(s) by which these receptors signal across membranes. Ultimately, we expect to understand the molecular basis for cellular trafficking, providing fundamental insights into crucial pathways involved in human protein folding diseases.

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Grant Details

Amount Awarded 3027479
Applicant Surname Newstead
Approval Committee Science Interview Panel
Award Date 2019-12-03T00:00:00+00:00
Financial Year 2019/20
Grant Programme: Title Collaborative Award in Science
Internal ID 219531/Z/19/Z
Lead Applicant Prof Simon Newstead
Other Applicant(s) Prof Francis Barr, Prof Markus Seeger, Prof Philip Biggin
Partnership Value 3027479
Planned Dates: End Date 2025-04-01T00:00:00+00:00
Planned Dates: Start Date 2020-04-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East