Abstract
SummarySpore formation in Bacillus subtilis relies on a regulated intramembrane proteolysis (RIP) pathway that synchronizes mother-cell and forespore development. To address the molecular basis of this SpoIV transmembrane signaling, we carried out a structure-function analysis of the activating protease CtpB. Crystal structures reflecting distinct functional states show that CtpB constitutes a ring-like protein scaffold penetrated by two narrow tunnels. Access to the proteolytic sites sequestered within these tunnels is controlled by PDZ domains that rearrange upon substrate binding. Accordingly, CtpB resembles a minimal version of a self-compartmentalizing protease regulated by a unique allosteric mechanism. Moreover, biochemical analysis of the PDZ-gated channel combined with sporulation assays reveal that activation of the SpoIV RIP pathway is induced by the concerted activity of CtpB and a second signaling protease, SpoIVB. This proteolytic mechanism is of broad relevance for cell-cell communication, illustrating how distinct signaling pathways can be integrated into a single RIP module.
Highlights
Cellular differentiation is a process commonly associated with multicellular organisms and their development
The final steps of spore formation are under control of the sigma factor sK, which is synthesized in the mother cell as an inactive, membrane-associated precursor protein that is activated by regulated intramembrane proteolysis (RIP) (Wolfe and Kopan, 2004)
Inhibition of 4FB is relieved by the signaling proteases SpoIVB (4B) and CtpB that are secreted into the intramembrane space and cleave the extracellular domain of the negative regulator 4FA at multiple sites (Campo and Rudner, 2006; Zhou and Kroos, 2005)
Summary
Cellular differentiation is a process commonly associated with multicellular organisms and their development. The final steps of spore formation are under control of the sigma factor sK, which is synthesized in the mother cell as an inactive, membrane-associated precursor protein (pro-sK) that is activated by regulated intramembrane proteolysis (RIP) (Wolfe and Kopan, 2004). In the specialized SpoIV RIP pathway, the I-CLiP intramembrane cleaving protease SpoIVFB (4FB) is embedded in the mother-cell membrane and is held inactive by two membrane proteins SpoIVFA (4FA) and BofA (Cutting et al, 1990; Resnekov and Losick, 1998; Rudner et al, 1999; Rudner and Losick, 2002). The 4FB membrane protease processes pro-sK into the mature sK transcription factor that, in turn, activates many of the genes required to complete the sporulation program (Campo and Rudner, 2006, 2007; Pan et al, 2003). Though the members of this specialized RIP pathway are known, it is still unclear how the distinct proteases cooperate with each other to ensure the precisely timed activation of sK
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