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Shan-Ho Chou
Shan-Ho Chou
National Chung Hsing University
The Wonderful Secondary Messenger Molecules Crucial for Bacterial Physiology


Cyclic di-GMP (c-di-GMP) has been found to be widely present in bacterial kingdom, acting as a secondary messenger to control many important cellular activities, such as biofilm formation, biogenesis and action of flagella and pili, and synthesis and secretion of pathogenic factors in diverse bacteria. C-di-GMP is generated by the GGDEF domain-containing diguanlyate cyclases and degraded by the EAL domain- or HD-GYP domain-containing phosphodiesterases. The mechanisms of c-di-GMP biosynthesis and degradation have been characterized in some detail. However, the nature of c-di-GMP receptors and the mechanisms of c-di-GMP-mediated regulation are still not fully understood. In the past several years, a variety of c-di-GMP-binding protein receptors and two RNA-based riboswitches have been described but it is clear that many more remain to be identified. 

In the past, the PilZ domain is possibly the most important c-di-GMP binding domain, and has been found to be present in association with many different protein domains to carry out a variety of c-di-GMP regulated processes. However, we have found that although PilZ or other reported c-di-GMP binding domains have been intensively studied, there are many bacteria that completely lack any such c-di-GMP binding domains. It indicates that there are other c-di-GMP binders that are not discovered yet. Recently, we have found one novel c-di-GMP binding domain that uses anintriguing binding modecompletely different to anyc-di-GMP binders reported to date. It exhibits a 53-residue motif for recognizing and binding c-di-GMP, using many hydrophobic residues that are highly conserved. It also uses unique peptide backbone amide protons to form two hydrogen-bonds with the c-di-GMP guanine via its Hoogsteen-edge. In addition, it exhibits a stronger binding affinity than PilZ domains, approximately ten fold stronger. Importantly, such a strong binding stems mostly from hydrophobic interactions, not via polar interactions. Thus the discovery of this novel c-di-GMP binding mode will sparkle the next phase of c-di-GMP research. 


S-HChou* and MY Galperin*. (review) Diversity of c-di-GMP-binding proteins and mechanisms. J Bacteriol. 2016;198:32-46. 

Yu-Chuan Wang et al.and Shan-Ho Chou*, Nucleotide binding by the widespread high-affinity cyclic di-GMP receptor MshEN domain, 2016, Nature Communications 7: 12481.

Dr. Shan-Ho Chou is currently a Chair Professor and Director of the Institute of Biochemistry, National Chung Hsing University, Taiwan. He received his bachelor degree in Chemistry from National Taiwan Normal University, a master degree in Biochemistry from National Taiwan University, and a Ph.D. in Chemistry from University of Washington in Seattle, WA. At the first stage of his research career, he studied unusual nucleic acid structures using NMR and found several stable nucleic acid structures different from Watson-Crick base-paired duplex, which were published in review papers in NAR and JMB. He then switched his interests to studying structural genomics of the plant pathogen Xanthomonas campestris by X-ray crystallography and solved several unique c-di-GMP-protein complex structures. He is now combining X-ray, NMR, and single particle cryo-EM techniques to study multidomain or membrane proteins associated with c-di-GMP and c-di-AMP binding. He is an author of more than 100 research papers, reviews, and book chapters.
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