Lecture 10.doc

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Microbiology (Biological Sciences)
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Nicolas Vozza

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Lecture 10 1 2 Component Systems II There is a wide array of different biological processes controlled by 2 C systems. The number of 2C systems in each bacterial species is highly variable Mycoplasma spp. : 0 (intracellular pathogen) Bacillus subtilus: 34 sets Haemophilus influenzae : 5 HPK; 4 RR Synechocystis : 38 sets E. coli : 28 sets Pseudomonas: 63 HPK; 64 RR But proteins with limited homology have been identified in Archea, Plants, Yeast, & mammalian mitochondria Thus, the phosphotransfer RXNs catalyzed by HPK & RRs represent an ANCIENT evolutionary signaling mechanism. Archaeal and eukaryotic 2CS have evolved through separate horizontal transfers of bacterial genes. Eukaryotic = hybrid type Archaea = classical P. aeruginosa 44 RRs: 24 = OmpR- like; 12 = FixJ-like; 8 = NtrC-like 20 others: Lecture 10 2 4 = CheB-like (output domain = esterase activ) 5 = CheY-like (no output domain) 11 = new RRs with conserved receiver domains, but output domains unrelated to known RR’s / each other 63 HPKs: 42/63 are classical IT > RR 5 = CheA-like (transmitter domain near N-term), Hpt-like 5 = Unorthodox: gene fusion with histidine-containing phosphotransfer module (Hpt): ITRHpt > RR Lecture 10 3 11 = Hybrid: these don’t contain an extended C term in receiver domain; phosphorelay between HPK & RR occurs with a separate Hpt module (dif protein) ITR > Hpt > RR Hpt module proteins – only 3 found in Pa. Genome / But 2/3 are found next to orphaned RR genes (orphaned genes do not have a known partner at that site on the genome. E.g. no sensor kinase at that site on the genome). Cognate HPK and RR pairs are usually found on genes located next to each other ; sometimes same Tn unit. Classical 2C genes function in same signaling pathway Predicts that orphaned atypical 2C genes function with more than one partner ie CROSSTALK The high number of atypical 2C systems is unique to Pa. (involved in 4 step phosphorelay) Maybe these offer checkpoints for phosphorylation rates Lecture 10 4 Phosphorylation Rate – controlled at 1. RR level – by specific phosphatases 2. at receiver module of RR by other more general phosphatases 3. Reverse Phosphorelay 4. In Pa., there are 11 HPK that seem to require Hpt modules, but there are only 3 Hpt modules. Bottleneck. How can this work? 1. There are other unknown Hpts with different AA sequences. 2. Maybe phosphoryl transfer does not always require an Hpt molecule. This would be unusual. Lecture 10 5 3. There are known examples where many hybrid kinases use the same Hpt. Summary 1. High number of 2C systems in Pa. 2. 16 atypical HPK (His-Asp phosphorelay) allows multiple regulatory checkpoints. 3. A 4 step phosphorelay by 3 proteins permits crosstalk 4. Different phosphatase members acting = lots of control Potential targets for Antimicrobial Therapy 1. 2C systems are widespread in bacteria, absent in mammals 2. by targeting select HKs or RRs, selective inhibition may be achieved (1 antibiotic  broad spectrum) Problem – most 2C systems are non-essential. BUT if you could shut down a few, due to their inter- dependence, you may be able to effect cellular shut-down 3. 2C systems are used by pathogenic bacteria to control expression of virulence factors. e.g. B pertussis BvgAS; S typhimurium PhoPQ. And resistance to antibiotics: S pneumoniae VncSR vancomycin Initia
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