A dichotomous family of Cache domain proteins evolved through c-type heme acquisition
Abstract
PAS domains often bind cofactors, whereas related Cache domains are thought to function exclusively as ligand-binding modules. We identify and characterize a large family of Cache domains containing covalently bound c-type heme. Sequence, phylogenetic and structual analysis of the DUF3365/Tll0287 family reveals conservation of a canonical CXXCH heme-binding motif, establishing c-type heme binding as a defining feature of this family. Despite previous annotation as PAS-like, these proteins share a distinct heme-binding insertion into a pre-existing Cache scaffold, representing the first documented recruitment of an intact cofactor-binding motif into a bacterial sensor domain. Domain architecture further divides the family into two subclasses: one exhibiting fusions to signaling domains and another comprised of standalone proteins. Spectroscopic analyses indicate that a representative signaling protein acts as a nitric oxide sensor, whereas a stand-alone representative exhibits redox-related properties and weak nitric oxide binding. These findings expand the functional repertoire of Cache domains and reveal a mechanism for the evolution of bacterial sensory systems.
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BibTeX
@article{deshpande2026dichotomous,
title = {{A dichotomous family of Cache domain proteins evolved through c-type heme acquisition}},
author = {Maithili Deshpande and Jiawei Xing and Vadim M. Gumerov and Robert Dunleavy and Herbert Castillo and Brian R. Crane and Igor B. Zhulin},
journal = {Communications Biology},
year = {2026},
month = nov,
doi = {10.1038/s42003-026-11299-1},
url = {https://www.nature.com/articles/s42003-026-11299-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A dichotomous family of Cache domain proteins evolved through c-type heme acquisition
AU - Maithili Deshpande
AU - Jiawei Xing
AU - Vadim M. Gumerov
AU - Robert Dunleavy
AU - Herbert Castillo
AU - Brian R. Crane
AU - Igor B. Zhulin
PY - 2026
DA - 2026/11/04
JO - Communications Biology
DO - 10.1038/s42003-026-11299-1
UR - https://www.nature.com/articles/s42003-026-11299-1
AB - PAS domains often bind cofactors, whereas related Cache domains are thought to function exclusively as ligand-binding modules. We identify and characterize a large family of Cache domains containing covalently bound c-type heme. Sequence, phylogenetic and structual analysis of the DUF3365/Tll0287 family reveals conservation of a canonical CXXCH heme-binding motif, establishing c-type heme binding as a defining feature of this family. Despite previous annotation as PAS-like, these proteins share a distinct heme-binding insertion into a pre-existing Cache scaffold, representing the first documented recruitment of an intact cofactor-binding motif into a bacterial sensor domain. Domain architecture further divides the family into two subclasses: one exhibiting fusions to signaling domains and another comprised of standalone proteins. Spectroscopic analyses indicate that a representative signaling protein acts as a nitric oxide sensor, whereas a stand-alone representative exhibits redox-related properties and weak nitric oxide binding. These findings expand the functional repertoire of Cache domains and reveal a mechanism for the evolution of bacterial sensory systems.
SN - 2399-3642
ER -