Evolutionarily divergent DUF4465 domains have a common vitamin B12-binding function

Clarke, Charlea, Banasik, Michal, Juodeikis, Rokas, Warren, Martin J. and Pickersgill, Richard W. (2026) Evolutionarily divergent DUF4465 domains have a common vitamin B12-binding function. FEBS Open Bio. ISSN 2211-5463

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Abstract

The DUF4465 family (DUF, domain of unknown function) contains more than 1000 members distributed across eight bacterial clades with species from diverse microenvironments including various gut microbiomes, hydrothermal vents, and soil. In the gut commensal Bacteroides thetaiotaomicron (B. theta), DUF4465 containing proteins act as high-affinity B12–binding proteins that scavenge this cofactor to ensure bacterial survival. Such B12 capture is essential for bacteria that have lost the ability to synthesize B12 de novo. This raises the question of whether B12-binding is ubiquitous across this family of proteins. Here, we show that B12-binding is a recurrent function of eight distantly related members of the DUF4465 family. It is reasonable to conclude that B12-binding is a common function of most DUF4465 proteins. These results establish DUF4465 as a structurally conserved family of augmented β-jellyroll B12-binding proteins with widespread roles in microbial competition for this essential cofactor. Impact statement DUF4465 defines a widespread, structurally conserved bacterial cobalamin-binding domain and provides a promising scaffold for protein-based B12 capture and purification.

Item Type:	Article
Additional Information:	Data accessibility: The structure and structure factors for DUF4465 protein D5EK51 are deposited in the protein databank (PDB) with code 9HMU.
Uncontrolled Keywords:	b-binding proteins,b-scavenging proteins,duf4465 (duf domain of unknown function),ipr027828 family proteins,microbiome,β-jellyroll proteins,general biochemistry,genetics and molecular biology ,/dk/atira/pure/subjectarea/asjc/1300/1300
Faculty \ School:	Faculty of Science
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
Related URLs:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	13 May 2026 14:49
Last Modified:	14 May 2026 15:16
URI:	https://ueaeprints.uea.ac.uk/id/eprint/103005
DOI:	10.1002/2211-5463.70231

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