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Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):E529-37. doi: 10.1073/pnas.1516930113. Epub 2016 Jan 19.

Intrinsic regulation of FIC-domain AMP-transferases by oligomerization and automodification.

Author information

1
Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
2
Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
3
Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
4
Research IT, Biozentrum, University of Basel, CH-4056 Basel, Switzerland;
5
Biophysics Facility, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
6
Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; christoph.dehio@unibas.ch sebastian.hiller@unibas.ch tilman.schirmer@unibas.ch.
7
Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; christoph.dehio@unibas.ch sebastian.hiller@unibas.ch tilman.schirmer@unibas.ch.

Abstract

Filamentation induced by cyclic AMP (FIC)-domain enzymes catalyze adenylylation or other posttranslational modifications of target proteins to control their function. Recently, we have shown that Fic enzymes are autoinhibited by an α-helix (αinh) that partly obstructs the active site. For the single-domain class III Fic proteins, the αinh is located at the C terminus and its deletion relieves autoinhibition. However, it has remained unclear how activation occurs naturally. Here, we show by structural, biophysical, and enzymatic analyses combined with in vivo data that the class III Fic protein NmFic from Neisseria meningitidis gets autoadenylylated in cis, thereby autonomously relieving autoinhibition and thus allowing subsequent adenylylation of its target, the DNA gyrase subunit GyrB. Furthermore, we show that NmFic activation is antagonized by tetramerization. The combination of autoadenylylation and tetramerization results in nonmonotonic concentration dependence of NmFic activity and a pronounced lag phase in the progress of target adenylylation. Bioinformatic analyses indicate that this elaborate dual-control mechanism is conserved throughout class III Fic proteins.

KEYWORDS:

AMPylation; adenylylation; enzyme regulation; molecular timer; posttranslational modification

PMID:
26787847
PMCID:
PMC4747691
DOI:
10.1073/pnas.1516930113
[Indexed for MEDLINE]
Free PMC Article

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