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bioRxiv · 10.64898/2026.08.18.745482

Rv0810c: a genus-conserved, structurally ordered small protein of unknown function carrying DUF3073 in Mycobacterium tuberculosis

Guyeux, C.
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Abstract

Small annotated open reading frames are the most neglected part of the functionally uncharacterised M. tuberculosis genome. We revisit Rv0810c, a 60-residue protein carrying the unknown-function domain DUF3073 (Pfam PF11273), flagged as an Actinobacteria-signature protein in 2006 but never studied since. Rv0810c is genuinely translated (detected in 11 of 16 M. tuberculosis proteomic datasets), with no significant human homologue, no neighbouring-gene overlap, and no CRISPR-interference polar effect on either flank. Residue-resolved confidence reveals a bipartite architecture: a rigid 33-residue module (pLDDT 91.9) followed by an extended, acidic, intrinsically disordered tail (radius of gyration 22.8 A against 11-12 A expected for a globular protein). The gene is under strong purifying selection (non-synonymous/synonymous ratio 0.86 against 1.93 among 74 size-matched controls, p=5.8x10-8), and its two commonest missense variants are each confined to one sub-lineage, indicating clonal expansion rather than relaxed constraint. DUF3073 is present without a single confirmed loss across 260 well-supported Actinomycetia genera. Despite this conservation, eight independent computational strategies, spanning sequence, structure, electrostatic-patch, embedding-similarity and homo-oligomerisation searches, converge on the same negative: no assignable fold, binding site, or functional neighbour in curated or uncurated sequence space. A phosphosite (Thr24), reproducibly reported by three laboratories, cannot be attributed to a kinase by chemical-genetic or sequence-motif evidence. The contradiction between predicted cytoplasmic topology and macrophage-secretory-fraction detection is narrowed, not resolved: ESX secretion, an immunodominant-epitope confound and host-induced transcription are excluded. Rv0810c exemplifies a class of genuinely uncharacterisable small proteins for which negative reporting, not a manufactured function, is the honest outcome.

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Guyeux, C.. 2026-08-19. Rv0810c: a genus-conserved, structurally ordered small protein of unknown function carrying DUF3073 in Mycobacterium tuberculosis. https://doi.org/10.64898/2026.08.18.745482

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