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bioRxiv · 10.64898/2026.08.06.743244

SYNTAX Reads the Motif and Domain Grammar of the Androgen Receptor Proximal Interactome

Eng, J. K.·Wright, M. E.
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Abstract

A receptors interactome is usually reported as a protein list, yet the sequence rules that organize it have never been read out. We introduce SYNTAX, a scan of 356 short linear motif classes and 573 protein domains that corrects the length, burden, and degeneracy artifacts of motif counting, and apply it to 4,751 androgen receptor (AR)-proximal interacting proteins (AR-PIPs) across three subcellular compartments and an androgen time course. ARs signature coactivator motif, LXXLL, is the most depleted class, while the neighborhood speaks a disorder-resident signaling vocabulary of SUMOylation sites, SPOP and SIAH degrons, and nuclear-import signals. The paradox resolves once incidental motifs are removed. ARs coactivator core forms a small, 9-fold-enriched inner shell within a signaling periphery. The grammar reproduces in an estrogen receptor-beta interactome (r = 0.89) and generalizes to the 5-HT2A serotonin receptor and EGFR. SYNTAX interfaces with the Predictive Proximal Proteome (PPP) Database, a queryable AR-PIP resource.

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Eng, J. K., Wright, M. E.. 2026-08-06. SYNTAX Reads the Motif and Domain Grammar of the Androgen Receptor Proximal Interactome. https://doi.org/10.64898/2026.08.06.743244

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