Group Leader/s

 

intro

Tubulin-like proteins spread in eukaryotes, bacteria, archaea, plasmids and viruses; they include microtubule αβ-tubulin, microtubule organizing γ-tubulin, primitive bacterial tubulin BtubA/B, bacterial cell division protein FtsZ, and the DNA-positioning TubZs codified by plasmid and phages, among other. They share a three-dimensional core structure, consisting of an N-terminal GTP binding domain and a GTPase activating domain connected by a central α-helix, but have divergent C-terminal secondary structures and disordered tails. Tubulin-like proteins frequently assemble head to tail into polar protofilaments with a 4 nm axial spacing between subunits that coalesce into different types of polymers, forming characteristic subcellular structures such as spindles or division rings. Assembly involves the formation of a subunit-subunit interface where the GTP-binding domain of one subunit in a protofilament interacts with the GTPase activation domain of the next subunit, which complements the GTP pocket and induces GTP hydrolysis. GTP hydrolysis triggers disassembly, which is coupled to free tubulin or FtsZ subunits switching back into inactive conformation. Their polymers show different dynamic features, such as dynamic instability or treadmilling, which can produce motility without the assistance of motor proteins. Tubulin is the target of antitumor drugs that impair microtubule dynamics; FtsZ assembly guides bacterial cell division, which is a target for the discovery of new antibiotics needed to fight resistant pathogens. 

Our work has focused on understanding how these protein assembly machines work, their self-organizing properties, how they evolved, and targeting them with small molecules, employing biochemical, crystallography, NMR, computational, microbiological, fluorescence, electron microscopy and synthetic approaches at the CIB and collaborating labs. We recently demonstated the FtsZ assembly switch with fluorescent probes that bind to the active FtsZ conformation in filaments rather than to the free subunits. The FtsZ switch together with GTP hydrolysis enables the filament treadmilling dynamics that in turn guides peptidoglycan synthesis during division. 

On the methodological side, our lab pioneered protein shape determination with synchrotron SAXS employing bead models and genetic algorithms. We developed fluorescence polarization screening assays for inhibitors binding to the taxane site of microtubules. We have also developed fluorescent assays and cell-based methods to screen GTP-replacing FtsZ inhibitors and new antibiotic leads.

Currently, I pursue collaborative research interests at CIB after my formal retirement. I value interdisciplinary research and enjoy biophysical methods and instrumentation.

Please see my research lines, timeline, collaborators, and former group members.

 

direct web address: http://www.cib.csic.es/tubulinas

contact: j.m.andreu@cib.csic.es

Google profile: http://scholar.google.es/citations?hl=en&user=FyBdDrgAAAAJ&view_op=list_works&sortby=pubdate

 

synthetic MciZ inhibits bacterial division

Artist view of FtsZ polymer architecture

 

 

                                          

  PC190723   GDP                     taxol   GDP                                                    TubZ from botulinum cs-t phage

Ligand binding cavities in FtsZ (left) and beta-tubulin (right)

 

 

 

Members

Staff Scientists
José Manuel Andreu Morales
group picture
 

Araújo-Bazán L, Huecas S, Valle J, Andreu D, Andreu JM  [2019]. Synthetic developmental regulator MciZ targets FtsZ across Bacillus species and inhibits bacterial division. Molecular Microbiology, 111, 865-980 & cover. doi: 10.1111/mmi.14198

Huecas S, Ramirez-Aportela E, Vergoñós A, Nuñez-Ramirez R, Llorca O, Diaz JF, Juan-Rodriguez D, Oliva M.A., Castellen P, Andreu JM.
 [2017]. 
Self-organization of FtsZ polymers in solution reveals spacer role of the disordered C-terminal tail. Biophysical J., 113, 1831-1844 & cover. doi: 10.1016/j.bpj.2017.08.046

Wagstaff J, Tsim M, Oliva MA, García-Sanchez A, Kureisaite-Ciziene D, Andreu JM, Löwe J  [2017]. A polymerisation-associated conformational switch in FtsZ that enables treadmilling. Mbio, 8, e00254-17. doi: 10.1128/mBio.00254-17

 

Funding

-Targeting bacterial cell division protein FtsZ with small molecules and fluorescent probes. BFU2014-51823-R (2015-2018).

-Discovery and validation of therapeutic targets CM S2010/BMD-2353 (2012-2016)

 

More info

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