Communications Biology· 2026Q1
A dichotomous family of Cache domain proteins evolved through c-type heme acquisition
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- Q1SCImago
- 2026year
Short summary
A novel family of bacterial Cache sensor domains has evolved to bind c-type heme, enabling them to function as nitric oxide sensors, a significant expansion of the known Cache domain repertoire.
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Key points
- A novel family of bacterial Cache domains (DUF3365/Tll0287) has been identified that covalently bind c-type heme.
- These domains possess a conserved CXXCH motif for heme binding and a Cache fold augmented by a heme-binding structural element.
- Heme-containing Cache domains are widely distributed in bacteria, particularly in Gracilicutes, and often function as stand-alone modules.
- Phylogenetic analysis suggests these domains evolved by inserting a cytochrome c-derived fragment into a pre-existing Cache scaffold.
- Functional studies indicate these domains act as nitric oxide sensors, not oxygen sensors.
AI-generated from the title and abstract; the full text is not read.
Abstract
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.
The authors' abstract, as published at the source. Communications Biology, 2026 · DOI ↗
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Field: Biochemistry (Biochemistry, Genetics and Molecular Biology)
BiochemistryBiochemistry, Genetics and Molecular Biology