---
title: "Short Linear Motifs Organize the Androgen Receptor Proximal Interactome via LXXLL and Two-Mode Eng"
id: "biorxiv-10-short-linear-motifs-as-a-general-organizing-principle-of-the-nuclear-receptor"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-10-short-linear-motifs-as-a-general-organizing-principle-of-the-nuclear-receptor"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.06.743235v1?rss=1"
published_at: "2026-08-06T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Short Linear Motifs Organize the Androgen Receptor Proximal Interactome via LXXLL and Two-Mode Eng
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-10-short-linear-motifs-as-a-general-organizing-principle-of-the-nuclear-receptor
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.06.743235v1?rss=1)
- **Published At:** 2026-08-06T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study mapped the proximal interactome of the **androgen receptor (AR)** using proximity-labeling quantitative mass spectrometry across cytosolic, microsomal, and nuclear compartments in LNCaP prostate cancer cells. - Prior AR-interactome catalogs listed roughly **1,000 AR-interacting proteins (AR-IPs)**; this work resolved **4,751 AR-proximal interacting proteins (AR-PIPs)**, expanding the proximal network more than fourfold. - The analysis anchored on the **LXXLL coactivator recognition motif** and assessed motif enrichment or depletion among AR-PIPs. - After controlling for protein length, **LXXLL motifs were systematically depleted** in AR-PIPs, a result the authors interpret as consistent with **low-affinity, transient** engagement at the AR **AF-2 charge clamp** rather than stable, high-affinity recruitment. - A subset of AR-PIPs that do contain LXXLL motifs includes AR itself and canonical AR coactivators; these proteins are noted to be altered (by amplification, deletion, or motif-spanning mutations) in metastatic and castration-resistant **prostate cancer**. - Comparison with the splice variant **AR-V7**, which lacks the AF-2 surface, showed retention of LXXLL-depleted Mode 1 partners and loss of the LXXLL-enriched Mode 2 cloud, supporting a **two-mode engagement framework** for nuclear receptor-proximal interactomes. - The proximal interactome measurements were compartment-resolved (cytosol, microsomes, nucleus), enabling detection of AR-proximal proteins across cellular locations. - The report is a preprint and has not undergone peer review. Funded in part by NIH R01GM143399; authors affiliated with University of Washington, National Jewish Health, and University of Iowa. - The authors declared no competing interests.
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Jimmy K Eng 1 University of Washington; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Jimmy%2BK%2BEng%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Eng%20JK&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AJimmy%2BK%2BEng%2B) Lilliana Radoshevich 2 National Jewish Health; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Lilliana%2BRadoshevich%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Radoshevich%20L&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ALilliana%2BRadoshevich%2B) Michael E Wright 3 University of Iowa * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Michael%2BE%2BWright%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Wright%20ME&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMichael%2BE%2BWright%2B) * [ORCID record for Michael E Wright](http://orcid.org/0000-0002-4243-2931 "Open in new tab") * For correspondence: michael-e-wright@uiowa.edu * [Abstract](https://www.biorxiv.org/content/10.64898/2026.08.06.743235v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5684189/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.08.06.743235v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5684189/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.08.06.743235v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5684189/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.08.06.743235v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5684189/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract 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. ### Competing Interest Statement The authors have declared no competing interest. ## Funder Information Declared National Institutes of Health, https://ror.org/01cwqze88, R01GM143399 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-NC-ND 4.0 International license](http://creativecommons.org/licenses/by-nc-nd/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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