AI Insight
Researchers used proximity-labeling mass spectrometry to identify 4,751 proteins that interact with or are near the androgen receptor (AR) in prostate cancer cells, revealing how this single receptor engages with numerous molecular partners. They discovered that AR uses two distinct modes of interaction: Mode 1 partners lack the LXXLL binding motif and engage independently of the AR AF-2 domain, while Mode 2 partners contain LXXLL motifs and require AF-2 for interaction. The AR-V7 splice variant, which lacks the AF-2 domain and is associated with treatment-resistant prostate cancer, retains only Mode 1 interactions, confirming this two-mode engagement framework.
Why it matters
This work provides a mechanistic explanation for how nuclear receptors organize large protein interaction networks and may help explain why AR-V7-expressing prostate cancers resist standard hormone therapies. Understanding these interaction modes could guide development of targeted therapies for castration-resistant prostate cancer by identifying which protein partnerships remain functional in treatment-resistant variants.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
The AR-interactome comprises ~1,000 androgen receptor-interacting proteins (AR-IPs), yet how a single receptor engages so many partners across compartments remains mechanistically unclear. We integrate proximity-labeling quantitative mass spectrometry across cytosolic, microsomal, and nuclear compartments of LNCaP prostate cancer cells and resolve 4,751 AR-proximal interacting proteins (AR-PIPs), more than four times the size of the AR-interactome. Anchoring on the LXXLL coactivator recognition motif, LXXLL motifs are systematically depleted in AR-PIPs after length control, consistent with low-affinity, transient engagement at the AR AF-2 charge clamp. LXXLL-bearing AR-PIPs include AR itself and canonical AR coactivators altered by amplification, deletion, or motif-spanning mutations in metastatic and castration-resistant prostate cancers. AR-V7, which lacks AF-2, retains LXXLL-depleted Mode 1 partners and loses the LXXLL-enriched Mode 2 cloud, thereby validating a two-mode engagement framework for nuclear receptor-proximal interactomes.
Source: Short Linear Motifs as a General Organizing Principle of the Nuclear-Receptor Proximal Interactome