TY - JOUR

T1 - Allosteric regulation of glycogen breakdown by the second messenger cyclic di-GMP

AU - Schumacher, Maria A.

AU - Wörmann, Mirka E.

AU - Henderson, Max

AU - Salinas, Raul

AU - Latoscha, Andreas

AU - Al-Bassam, Mahmoud M.

AU - Singh, Kumar Siddharth

AU - Barclay, Elaine

AU - Gunka, Katrin

AU - Tschowri, Natalia

N1 - Funding Information: Research in Natalia Tschowri’s lab is funded by the DFG Emmy Noether-Program (TS 325/1-1) and the DFG Priority Program SPP 1879 (TS 325/2-2). We thank Stephen Bornemann for providing strains, Julia Schneider for technical assistance and the research core unit metabolomics at the Hannover Medical School for support with LC-MS/MS analysis. We acknowledge Alison M. Smith, Karl Forchhammer, and Niels Neumann for scientific consultation. We thank Kim Findlay of the JIC Bioimaging facility for assisting with the electron microscopy and Neil Holmes for handling the samples. The research in the Schumacher lab was supported by National Institutes of Health grants (R35GM130290). We acknowledge beamline 5.0.2 and 5.0.1 for X-ray diffraction data collection. The ALS (Berkeley, CA) is a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the US Department of Energy under Contract DE-AC02-05CH11231, Office of Basic Energy Sciences. Beamline 5.0.2 and 5.0.1 of the ALS, a US Department of Energy Office of Science User Facility under Contract DE-AC02-05CH11231, is supported in part by the ALS-ENABLE program funded by the NIH, National Institute of General Medical Sciences, Grant P30 GM124169-01.

PY - 2022/12

Y1 - 2022/12

N2 - Streptomyces are our principal source of antibiotics, which they generate concomitant with a complex developmental transition from vegetative hyphae to spores. c-di-GMP acts as a linchpin in this transition by binding and regulating the key developmental regulators, BldD and WhiG. Here we show that c-di-GMP also binds the glycogen-debranching-enzyme, GlgX, uncovering a direct link between c-di-GMP and glycogen metabolism in bacteria. Further, we show c-di-GMP binding is required for GlgX activity. We describe structures of apo and c-di-GMP-bound GlgX and, strikingly, their comparison shows c-di-GMP induces long-range conformational changes, reorganizing the catalytic pocket to an active state. Glycogen is an important glucose storage compound that enables animals to cope with starvation and stress. Our in vivo studies reveal the important biological role of GlgX in Streptomyces glucose availability control. Overall, we identify a function of c-di-GMP in controlling energy storage metabolism in bacteria, which is widespread in Actinobacteria.

AB - Streptomyces are our principal source of antibiotics, which they generate concomitant with a complex developmental transition from vegetative hyphae to spores. c-di-GMP acts as a linchpin in this transition by binding and regulating the key developmental regulators, BldD and WhiG. Here we show that c-di-GMP also binds the glycogen-debranching-enzyme, GlgX, uncovering a direct link between c-di-GMP and glycogen metabolism in bacteria. Further, we show c-di-GMP binding is required for GlgX activity. We describe structures of apo and c-di-GMP-bound GlgX and, strikingly, their comparison shows c-di-GMP induces long-range conformational changes, reorganizing the catalytic pocket to an active state. Glycogen is an important glucose storage compound that enables animals to cope with starvation and stress. Our in vivo studies reveal the important biological role of GlgX in Streptomyces glucose availability control. Overall, we identify a function of c-di-GMP in controlling energy storage metabolism in bacteria, which is widespread in Actinobacteria.

UR - http://www.scopus.com/inward/record.url?scp=85139144731&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-33537-w

DO - 10.1038/s41467-022-33537-w

M3 - Article

C2 - 36192422

AN - SCOPUS:85139144731

VL - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5834

ER -