Controlling peptidoglycan synthesis from within the cell

Conferences and traveling are brilliant ways to meet new people and to commence new collaborations, as well as cementing old friendships. My lab started working on GpsB in earnest about 5 years ago after having a chat with Sven Halbedel over a beer (or two...) in the garden of the Grand Hotel La Pace in Montecatini Terme, Italy.

Jan 16, 2019
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We had both been attending the biennial conference on Gram-positive Microorganisms (save the date: July 23rd-26th 2019 for the next meeting in this series http://meetings.umd.edu/gram-pos/) and Sven’s proposal was extremely timely given my lab were finalising experiments on another cell division regulator called EzrA, which was eventually published in 2014 [1]. Incidentally, that EzrA paper was co-authored by Australian scientists Liz Harry, whom I’d first met at the same conference series >20 years ago, and Nick Dixon who I met for the first time in 2005 at a mutual friend’s house in Auckland, New Zealand. The power of travel!

Since 2013, Sven’s lab and mine have worked closely together on GpsB from Listeria monocytogenes and Bacillus subtilis, publishing a couple of quite nice papers [2,3] and helping to underpin funding in our labs. No doubt these collaborative studies also helped pave the way for Sven’s student Jeanine Rismondo to obtain a post-doc position in Imperial College, London. In other joint work, Sven’s student Sabrina Wamp and my student, Zoe Rutter, are combining their microbiology, genetics, biochemical and structural expertise on.... ah, sorry, can’t tell you that just now, you’ll have to wait for another day to hear of a new exciting story from our labs.

Back to GpsB: I met Orietta Massidda when she visited Newcastle in the summer of 2015, and discovered a shared interest in GpsB, amongst other proteins, and finally met Malcolm Winkler and Tiffany Tsui at an EMBO workshop in Prague, the Czech Republic, in September 2016. At this point, my brilliant post-doc, Rob Cleverley, had already amassed quite a lot of structural, biophysical and biochemical data on GpsB interactions with peptidoglycan synthases from B. subtilis (long-held as the Gram-positive paradigm and the focus of much of my own research for ~25 years) and L. monocytogenes (Figure 1). But Orietta, Malcolm and Tiffany all work on Streptococcus pneumoniae, and the published data on GpsB in this organism had yet to reach convergence. So a new partnership was born, with a stated ambition to consolidate our various expertises on our favourite model organisms, to try and determine the common rules dictating GpsB function.



Figure 1. We use 3D printed models of protein structures as a teaching tool and in outreach activities. Here the GpsB protein surface is coloured by electrostatics, red for negative and blue for positive, and the little silver discs are magnets (left hand image) that help stick the peptidoglycan synthase peptide to GpsB. There is perfect shape and charge complementarity that explains the exquisite selectivity of the interaction (right hand image). Simpler colour schemes are also readily available (hence the orange peptide) and you should contact Darren Gowers at www.molecmodels.co.uk if you are interested in 3D-printed models of your own.

The upshot of these face-to-face meetings is this paper [https://rdcu.be/bg9k9], published today by Nature Communications [4]. However, and at the risk of sounding like a Remoaner, this story would not have been possible without free movement of people, especially early career researchers, across Europe’s borders. Sven had been a post-doc in Newcastle when we first met before returning home to Germany; Jeanine left Germany to come to the UK to work in London and Federico Corona left sunny Sardinia for the northern cool of Newcastle. I do worry what influence the ‘hostile environment’ and the events yet to unfold after 29th March 2019, but after last night's calamitous defeat for the Government's Brexit plans who knows, will have on the UK’s ability to attract bright young minds to live amongst us as equals, work in our Universities and produce collaborative papers such as this [https://rdcu.be/bg9k9]....

References

1. Cleverley RM, Barrett, JR, Baslé A, Bui NK, Hewitt L, Solovyova A, Xu ZQ, Daniel, RA, Dixon NE, Harry EJ, Oakley AO, Vollmer W, Lewis RJ (2014) Structure and function of a spectrin-like regulator of bacterial cytokinesis. Nature Communications 5, 5421.

2. Rismondo J, Cleverley RM, Lane HV, Großhennig S, Steglich A, Möller L, Mannala GK, Hain T, Lewis RJ, Halbedel S. (2016) Structure of the bacterial cell division determinant GpsB and its interaction with penicillin binding proteins. Molecular  Microbiology 99, 978-998.

3. Cleverley RM, Rismondo J, Lockhart-Cairns MP, van Bentum PT, Egan A, Vollmer W, Halbedel S, Baldock C, Breukink E, Lewis RJ (2016) Subunit arrangement in GpsB, a regulator of cell wall biosynthesis. Microbial Drug Resistance 22, 446-60.

4.Cleverley RM, Rutter ZJ, Rismondo J, Corona F, Tsui H-CT, Alatawi FA, Daniel RA, Halbedel S, Massidda O, Winkler ME, Lewis RJ (2019) The cell cycle regulator GpsB functions as cytosolic adaptor for multiple cell wall enzymes. Nature Communications 10, 261.


Rick Lewis

Professor, Newcastle University

I'm a structural biologist who has an interest in understanding at the molecular level how bacteria grow and divide. Part of both division and growth cycles depend upon communication across the cytoplasmic membrane so that essential activities on the outside of the bacterial cell are co-ordinated with intracellular events. I have been at Newcastle University since 2003, after establishing then overseen the growth of structural biology within the University.

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