Biology subjects

Gumerov, V. M.

Publications and source records attributed to Gumerov, V. M..

7 recordsLinked to original sources

bioRxiv2026

A bacterial NO-binding sensor domain evolved through acquisition of a cytochrome-derived c-type heme-binding motif

Diverse bacterial sensory domains detect intracellular and extracellular cues and relay this information to downstream signaling pathways. Per-Arnt-Sim (PAS) domains are well known to bind cofactors such as heme for intracellular sensing, whereas Cache domains - the largest family of bacterial extracytoplasmic sensor modules - are thought to function exclusively as cofactor-independent ligand-binding domains. Here, we identify and characterize a large family of Cache domains that contain a covalently bound c-type heme. Systematic sequence analysis of the DUF3365/Tll0287 family of unknown function reveals exceptional conservation of a canonical CXXCH heme-binding motif, establishing c-type heme binding as a defining feature of this domain family. Structure- and sequence-based comparisons demonstrate that, despite prior annotation as PAS-like, these domains belong to the Cache superfamily and share a conserved Cache fold augmented by a distinct structural element harboring the heme-binding motif. Heme containing Cache domains are widely distributed across bacterial phyla, with strong enrichment in Gracilicutes, and frequently occur as stand-alone modules, an atypical presentation of Cache domains. Phylogenetic analyses support insertion of a short cytochrome c-derived fragment containing the heme-binding motif into a preexisting Cache scaffold, representing a previously unrecognized mode of sensor-domain evolution. Spectral and ligand-binding analyses indicate that heme containing Cache domains fused to signal-transduction modules have properties typical of nitric oxide, but not oxygen, sensors; whereas stand-alone domains likely have redox-related roles. Our findings expand the functional repertoire of Cache domains to include covalently bound cofactors and reveal fragment-level recruitment of enzymatic motifs as a route for the emergence of bacterial sensory systems.

microbiology↗

bioRxiv2025

Specificities of Chemosensory Receptors in the Human Gut Microbiota

The human gut is rich in metabolites and harbors a complex microbial community, yet the sensory repertoire of its commensal bacteria remains largely uncharacterized. Here we systematically mapped ligand specificities of extracytoplasmic sensory domains from twenty members of the human gut microbiota, with a primary focus on the abundant and physiologically important class of Clostridia. We identified diverse metabolites as specific stimuli for three major functional classes of transmembrane receptors. We further characterized novel subsets of sensors belonging to the Cache superfamily, specific for lactate, dicarboxylic acids, and for uracil and short-chain fatty acids (SCFAs), respectively, and investigated the evolution of their ligand specificity. Structural and biochemical analysis of the newly described dCache_1UR domain revealed an independent binding of uracil and SCFA at distinct modules. Altogether, we could identify or predict specificities for over a half of the Cache-type chemotactic sensors in the selected gut commensals, with the carboxylic acids representing the largest class of ligands. Among those, the most commonly found specificities were for lactate and formate, indicating particular importance of these metabolites in the human gut microbiome and consistent with their observed beneficial impact on the growth of selected bacterial species.

microbiology↗

bioRxiv2023

Ubiquitous purine sensor modulates diverse signal transduction pathways in bacteria

Purines and their derivatives are key molecules for controlling intracellular energy homeostasis and nucleotide synthesis. In eukaryotes, including humans, purines also act as signaling molecules that mediate extracellular communication and control key cellular processes, such as proliferation, migration, differentiation, and apoptosis. However, the signaling role of purines in bacteria is largely unknown. Here, by combining structural and sequence information, we define a purine-binding motif, which is present in sensor domains of thousands of bacterial receptors that modulate motility, gene expression, metabolism and second messenger turnover. The screening of compound libraries and microcalorimetric titrations of selected sensor domains validated their ability to specifically bind purine derivatives. The physiological relevance of purine sensing was demonstrated in a second messenger signaling system that modulates c-di-GMP levels.

microbiology↗

bioRxiv2023

Origin and functional diversification of PAS domain, a ubiquitous intracellular sensor

Signal perception is a key function in regulating biological activities and adapting to changing environments. PAS domains are ubiquitous sensors found in diverse receptors in bacteria, archaea, and eukaryotes, but their origins, distribution across the tree of life, and extent of their functional diversity remain unknown. Here, we show that using sequence conservation and structural information it is possible to propose specific and potential functions for a large portion of nearly 3 million PAS domains. Our analysis suggests that PAS domains originated in bacteria and were horizontally transferred to archaea and eukaryotes. We reveal that gas sensing via a heme cofactor evolved independently in several lineages, whereas redox and light sensing via FAD and FMN cofactors have the same origin. The close relatedness of human PAS domains to those in bacteria provides an opportunity for drug design by exploring potential natural ligands and cofactors for bacterial homologs. TeaserSignaling domains that originated in bacteria hold a potential as drug targets in humans.

evolutionary biology↗

bioRxiv2023

Amine recognizing domain in diverse receptors from bacteria and archaea evolved from the universal amino acid sensor

Bacteria contain many different receptor families that sense different signals permitting an optimal adaptation to the environment. A major limitation in microbiology is the lack of information on the signal molecules that activate receptors. Due to a significant sequence divergence, the signal recognized by sensor domains is only poorly reflected in overall sequence identity. Biogenic amines are of central physiological relevance for microorganisms and serve for example as substrates for aerobic and anaerobic growth, neurotransmitters or osmoprotectants. Based on protein structural information and sequence analysis, we report here the identification of a sequence motif that is specific for amine-sensing dCache sensor domains (dCache_1AM). These domains were identified in more than 13,000 proteins from 8,000 bacterial and archaeal species. dCache_1AM containing receptors were identified in all major receptor families including sensor kinases, chemoreceptors, receptors involved in second messenger homeostasis and Ser/Thr phosphatases. The screening of compound libraries and microcalorimetric titrations of selected dCache_1AM domains confirmed their capacity to specifically bind amines. Mutants in the amine binding motif or domains that contain a single mismatch in the binding motif, had either no or a largely reduced affinity for amines, illustrating the specificity of this motif. We demonstrate that the dCache_1AM domain has evolved from the universal amino acid sensing domain, providing novel insight into receptor evolution. Our approach enables precise "wet"-lab experiments to define the function of regulatory systems and thus holds a strong promise to address an important bottleneck in microbiology: the identification of signals that stimulate numerous receptors.

microbiology↗

bioRxiv2021

Amino acid sensor conserved from bacteria to humans

Amino acids are recognized as signals by various receptors in bacteria, archaea, and eukaryotes. However, no common mechanism for amino acid recognition is currently known. Here we show that a subclass of a ubiquitous extracellular domain dCache_1 contains a simple amino acid recognition motif, and it is found throughout the Tree of Life. In bacteria, this motif exclusively binds amino acids, including GABA, and it is present in all major receptor types. In humans, this motif is found in 2{delta} subunits of voltage-gated calcium channels that are implicated in neuropathic pain and neurodevelopmental disorders. Our findings suggest that GABA-derived drugs bind to the same motif in human 2{delta} subunits that binds natural GABA ligands in bacterial chemoreceptors.

evolutionary biology↗

bioRxiv2021

Phyletic distribution and diversification of the Phage Shock Protein stress response system in bacteria and archaea

The bacterial cell envelope is an essential structure that protects the cell from environmental threats, while simultaneously serving as communication interface and diffusion barrier. Therefore, maintaining cell envelope integrity is of vital importance for all microorganisms. Not surprisingly, evolution has shaped conserved protection networks that connect stress perception, transmembrane signal transduction and mediation of cellular responses upon cell envelope stress. The phage shock protein (PSP) stress response is one of such conserved protection networks. Most of the knowledge about the Psp response comes from studies in the Gram-negative model bacterium, Escherichia coli where the Psp system consists of several well-defined protein components. Homologous systems were identified in representatives of Proteobacteria, Actinobacteria, and Firmicutes; however, the Psp system distribution in the microbial world remains largely unknown. By carrying out a large-scale, unbiased comparative genomics analysis, we found components of the Psp system in many bacterial and archaeal phyla and demonstrated that the PSP system deviates dramatically from the proteobacterial prototype. Two of its core proteins, PspA and PspC, have been integrated in various (often phylum-specifically) conserved protein networks during evolution. Based on protein sequence and gene neighborhood analyses of pspA and pspC homologs, we built a natural classification system of PSP networks in bacteria and archaea. We performed a comprehensive in vivo protein interaction screen for the PSP network newly identified in the Gram-positive model organism Bacillus subtilis and found a strong interconnected PSP response system, illustrating the validity of our approach. Our study highlights the diversity of PSP organization and function across many bacterial and archaeal phyla and will serve as foundation for future studies of this envelope stress response beyond model organisms.

microbiology↗