19-BBSRC-NSF/BIO. Leveraging synthetic biology to probe the rules of cell morphogenesis.
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
This project seeks to understand how cells control their shape and movement using synthetic tools. Cell movement is essential for single cells to hunt and mate and for the correct development and function of multicellular organisms. Sheet-like protrusions called lamellipodia are the engines that power and guide this motility. However, the rules of their formation are not understood. Similar to ant colonies where no individual is "in charge", and the overall behaviours of a colony depends on simple rules of local interaction between ants, many aspects of cell biology are dominated by local rules of interaction between proteins. This project seeks to define these rules of protein-protein interactions by constructing lamellipodia from synthetic, designer proteins whose patterns of interaction can be built to order. This work is a collaboration between an expert in cell shape/movement (Weiner) and an expert in protein design (Woolfson). This work is necessarily multidisciplinary and it will train three postdoctoral fellows to work together across cell biology, protein design and biophysics. This work will strengthen links between US and UK labs and between the NSF and the BBSRC.
Technical Summary
Weiner's lab recently discerned the nanoscale organization of a key actin nucleator that suggests a self-organizing template for lamellipodia formation. These templates are not sufficiently understood to manipulate directly their biophysical parameters (such as linearity vs. curvature, rigidity, dynamics, etc.) and to probe fully the relation between actin nucleator oligomerization and cell shape and function. A powerful alternative to the typical genetic and biochemical approaches would be to build actin regulators from scratch, so that the molecular logic of cell shape and movement can be probed systematically. To do this, protein engineering and de novo protein design (Woolfson lab) will be used to generate synthetic proteins that assemble with defined geometries at membranes to nucleate actin, guided by our knowledge of the native system. These synthetic systems will be tested for their ability to support lamellipodial formation in vivo using cells defective in lamellipodia formation and ultimately in complete reconstitutions. These studies will advance protein design towards in-cell application, and, in turn, they will help define the molecular logic of cell shape and movement.
People |
ORCID iD |
Dek Woolfson (Principal Investigator) |
Publications
Woolfson DN
(2023)
Understanding a protein fold: The physics, chemistry, and biology of a-helical coiled coils.
in The Journal of biological chemistry
Naudin EA
(2022)
From peptides to proteins: coiled-coil tetramers to single-chain 4-helix bundles.
in Chemical science
Hilditch AT
(2024)
Maturation and Conformational Switching of a De Novo Designed Phase-Separating Polypeptide.
in Journal of the American Chemical Society
Cross JA
(2024)
A de novo designed coiled coil-based switch regulates the microtubule motor kinesin-1.
in Nature chemical biology
Albanese KI
(2024)
Rationally seeded computational protein design of ?-helical barrels.
in Nature chemical biology
Description | UCSF-Bristol Collaboration |
Organisation | University of California, San Francisco |
Department | Cardiovascular Research Institute (CVRI) |
Country | United States |
Sector | Academic/University |
PI Contribution | This is a joint NSF-BBSRC grant between UCSF and Bristol. Currently, it employs 2 PDRAs at Bristol and 1 graduate student at UCSF, and brings in broader teams from both institutes. We hold monthly catch-up meetings by zoom and share reagents by post. |
Collaborator Contribution | See above. |
Impact | None yet. It is year 1 of a 5-year programme. |
Start Year | 2021 |
Description | Speaker at Somerscience Festival 2023 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Dek Woolfson spoke to a mixed audience of about 20+ people in Bruton Church on May 1, 2023 as part of the Somerscience Festival. It was a short time to allow lots of time for questions, discussion, and engagement. |
Year(s) Of Engagement Activity | 2023 |
URL | https://somerscience.co.uk/ |