Exploring structure and function of FtsZ, a prokaryotic cell division protein and tubulin-homologue

by G.J. McCool, a graduate student in the Department of Microbiology,
at the University of Massachusetts, Amherst.
A student in the lab of M. C. Cannon.

images / schematics


       Most prokaryotes divide by a process called 'binary fission', whereby one cell gives rise to two daughter cells which are essentially identical with respect to their physiology and genetic content. During vegetative growth of rod-shaped bacteria like Escherichia coli and Bacillus subtilis, a septum forms at the midpoint of a pre-divisional cell, which ultimately pinches off giving rise to two progeny cells. The septum is formed through the inward growth of cytoplasmic membrane and cell wall material that invaginates from opposing directions at the central plane of the cell (2, 7) . This seemingly simple event is in reality highly complex. It is a tightly regulated process that involves spatial and temporal controls that function to coordinate the physiological status of the cell, the replication of the chromosome, and chromosomal segregation with cellular division (2, 7). Much concerning the regulatory mechanisms that coordinate the cell cycle and timing of division, as well as many aspects of the division process itself, remains elusive and a clearer understanding of these processes is desirable (4).

       It is known for many bacteria that there are ten's of proteins required for cell division, most of which exact functions are still unknown (4). For instance, in Escherichia coli, a culmination of studies have shown that at least nine essential genes are required for proper septation and that the products of all nine genes (ftsA,ftsI,ftsK, ftsL,ftsN,ftsQ,ftsW,ftsZ,and zipA) have been shown to localize to the division plane during septation (7-15). From this group of proteins, FtsZ is the best characterized and most thoroughly-studied cell division protein (4). It appears to act at the earliest step in septation and is required through the final step of cytokinesis (8). In E. coli, it is the target of seven endogenous division inhibitors, including SulA of the SOS response, and its action in the cell likely represents a key step of commitment for the cell to engage in the division process (4, 7). FtsZ localizes to a yet-to-be defined nucleation site (see schematic) at the mid-point of the cell soon after daughter cell formation and assembles as a ring (FtsZ- or simply Z-ring) that remains associated with the cytoplasmic membrane (17) (see FtsZ movie). This subcellular organelle, a functional analog of the contractile ring used in cytokinesis of many eukaryotic cells, is thought to form the scaffold for recruitment of other key cell division proteins (e.g. FtsL localization). Its fundamental importance in cellular division is evident by its widespread occurrence in eubacteria, archeae, and some eukaryotic organelles and it has been suggested that FtsZ functions as the universal prokaryotic division protein (7). An alternative view of the function of FtsZ, as argued by Erickson (14), is that FtsZ forms the 'motor' of cell division, providing the force required for septum formation. This view is strengthened by the finding that FtsZ is the only cell division protein common to both Mycoplasma genetalium(with a minimal genome) and bacteria like E. coliand Bacillus subtilis. Since mycoplasmas lack any of the additional cell division proteins found in other bacteria, FtsZ may in fact represent the minimal component that in itself is capable of driving cell division. It was proposed that the force required for constriction of the growing septum might be provided by conformational changes in FtsZ protofilaments (straight to curved) induced by its inherent GTPase activity (14). Therefore, additional proteins like FtsQ, FtsL, and FtsW (etc.) that are found in bacteria like E. coliand B. subtilis, might instead function as specialized accessory proteins that may regulate or refine the division process, as opposed to force-generating components of the division machinery (14).

       A relatively new and interesting finding is that FtsZ and tubulin appear to be homologues (3, 17, 20). Tubulin, the key component of eukaryotic microtubules, are nearly universal among eukaryotes and are involved in various cellular functions such as intracellular trafficking, motility, and cell division (1, 20). This idea was first suggested following the initial observation that FtsZ contained the tubulin signature GTP-binding sequence motif, GGGTG(T/S)G (5, 17). This prompted biochemical analysis of FtsZ, which revealed that it too, like tubulin, had a GTPase activity (17, 19). Subsequently, it was also found that it could assemble into protofilaments, two-dimensional sheets, and protofilament rings in in vitrostudies, which was consistent with FtsZ having a cytoskeletal-like function (9). Early conclusions from sequence alignments between FtsZ and tubulin lead to a growing notion that these two proteins were homologous, at least over their GTP-binding domains. It was found that they shared substantial sequence identity over their N-terminal GTP-binding domains, but that there was a complete lack of sequence identity over their C-terminal domains. Overall, sequence identity between FtsZs and tubulins is less than 20% (21). Convincing evidence supporting the evolutionary relatedness of FtsZ and tubulin came to light when atomic structures of both proteins recently became available (5, 20). Subsequently, it was discovered through structural alignments that not only were the N-terminal domains almost identical in structure, but there was also significant structural identity over the core C-terminal domains (3). This was an unexpected finding because of the absence of sequence similarity over these regions. Furthermore, it was found that the GTP-binding domain of FtsZ/tubulin are clearly homologous to the GTP-binding domains of other typical GTPase proteins (like p21Ras), which contain Rossman fold structures for GTP-binding (3). Again, this was a surprise because of the lack of sequence homology between the GTP-binding domains of FtsZ/tubulin and other GTPase proteins (3). Therefore, although the sequences involved in nucleotide binding in FtsZ/tubulin are different than those in most GTPase proteins, the similarities between their structures suggest that they are related. Erickson (3) suggested a possible explanation which would account for the different nucleotide binding motifs found in FtsZ/tubulin and most GTPase proteins and the evolutionary relatedness of FtsZ and tubulin. It was speculated that an ancestral protein containing a Rossman fold-like GTP-binding domain diverged in two directions. In one direction it evolved into the typical GTPase family of proteins and in the other, into the atypical GTPase proteins FtsZ and tubulins (3). Alternatively, the similarity in structure between FtsZ and tubulin could be coincidental and there may not exist true homology between these proteins (21). Nevertheless, it is intriguing to think about the evolutionary history that most likely exists between FtsZ and tubulin and especially to wonder, Could FtsZ be the evolutionary precursor to tubulin and microtubules (1, 16)? (see diagram)

All Introduction Images and Schematics:

  • 1. Septum in a dividing cell (TEM).
  • 2. Schematic of FtsZ function during cell division.
  • 3. FtsL::GFP chimera protein localized as a ring in vivo.
  • 4. Time-lapse FtsZ localization and self-assembly.
  • 5. FtsZ/tubulin sequence alignment.
  • 6. Evolutionary history of FtsZ and tubulin.

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