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Periodic Report Summary 2 - AMEMM (Assembly, Mechanism, and Evolution of Macromolecular Machinery)

This document outlines progress made under my four-year FP7 CIG 'AMEMM' (Grant Agreement Number 630988). The proposal as originally submitted described my aims to understand the assembly, mechanism, and evolution of molecular machines. To accomplish this, I proposed a hybrid approach, incorporating 3D in situ electron cryo-tomographic imaging to visualize the structure of the machinery, biophysics to assess the mechanical output of the machinery, and molecular phylogenetics to contextualize these observations against a robust phylogeny. Three broad aims were proposed: first, I described aims to develop methods to structural characterize molecular machinery, using the bacterial flagellar motor and type III secretion systems as the model system. Secondly, I described aims to relate the structures of these macromolecular machines to their mechanical output. Thirdly, I outlined strategies to relate these results to phylogenetics of the component proteins towards understanding the mechanistic aspects of their evolution.

Scientific progress throughout the CIG period was excellent, and I accomplished the majority of my aims over the four years. I have published work on the structure of diverse flagellar motors, their phylogeny, and directly related these structures to their mechanical output. I have recruited a four postdocs over the course of the CIG to study the diverse bacterial flagellar motors and the analogous archaellar motor toward broad cross-species and cross-system comparative studies to flesh out fundamental principles of molecular evolution. We anticipate that these phylogenies will enable us to contextualize and interpret the evolutionary events behind diversification of flagellar motors; these insights, we believe, will be generally applicable to molecular evolution in general. I have also worked towards developing a pseudo-atomic model of the flagellar type III secretion system with a PhD student in lab.

In addition to scientific progress I contributed a major technical advance by constructing a roboticized system that enables routine overnight high-throughput electron cryo-tomographic data collection on a mid-range electron microscope. This development has been greeted with excitement by many members of the community, and enabled collection of large volumes of data towards major papers published in PNAS, Science, PLoS Biology, and Scientific Reports, with a number of other publications currently in preparation.

As a result, my research career development has progressed extremely well. Since award of the CIG I have been awarded six additional pieces of grant funding in total providing over £1 500 000 of funds to my lab. I have published a number of papers including the PNAS, Science, PLoS Biology, and Scientific Reports papers, many of which have received considerable press coverage from the mainstream media, and I have delivered, or am invited to deliver, over thirty talks on this work at major conferences. I have recruited four postdocs and four PhD students. These successes have lead me to pass the probationary period at Imperial College and be promoted to Senior Lecturer.

Reported by

IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
United Kingdom

Subjects

Life Sciences
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