bims-cutpro 2026-01-18 papers

Issue of 2026–01–18
four papers selected by
James M. Krieger, Francis Crick Institute

J Am Chem Soc. 2026 Jan 13.

Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation.

Aileen Frost, Suzanne O'Connor, Alessio Ciulli.

Proteolysis-targeting chimeras (PROTACs) have transformed the concept of chemical intervention in biological systems by co-opting the ubiquitin-proteasome system to selectively degrade proteins. A key promise of this modality is that proximity alone─not inhibition─is required, allowing binding anywhere on the protein surface to trigger degradation. Yet despite this conceptual freedom, most PROTACs to date have been built from orthosteric inhibitors. The use of allosteric or functionally silent ligands remains a largely untapped opportunity. In this Perspective, we spotlight pioneering efforts in allosteric PROTAC design and explore how such strategies could unlock improved outcomes for target selectivity, efficacy, and resistance management while also modulating physicochemical properties to enhance in vivo performance. We further discuss the practical and conceptual challenges and the advances needed to make allosteric targeting a mainstream strategy in the design of protein degraders and other proximity-inducing molecules.

DOI: https://doi.org/10.1021/jacs.5c14840

bioRxiv. 2026 Jan 07. pii: 2026.01.07.698128. [Epub ahead of print]

Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation.

Lin Zhang, Arnold Bolomsky, Omar S Al-Odat, Callie VanWinkle, Aaliyah Battle, Papiya Chakraborty, Ronald J Holewinski, Thorkell Andresson, Qingcai Meng, James D Phelan, Jagan Muppidi, Ryan M Young.

Oncogenic KRAS and NRAS mutations are common in hematologic malignancies, but how they signal is less well characterized than in carcinomas. To uncover novel RAS biology and potential therapeutic vulnerabilities, we employed a multi-omics screening approach in multiple myeloma to identify regulators of RAS activity. We report that the phosphatase PP1C dephosphorylates the conserved T148 residue on RAS, which in turn permits LZTR1-dependent proteasomal degradation. Notably, LZTR1 is ineffective against KRAS A146 gain-of-function mutations, which are adjacent to T148 and prevalent in hematologic cancers. Remarkably, we find that KRAS protein is four-fold less stable in hematologic versus carcinoma cells, offering a unique therapeutic opportunity targeting RAS protein stability mechanisms. The kinases PAK1 and PAK2 shield RAS from LZTR1-dependent degradation by phosphorylating T148, and targeting PAK1/2 activity improves RAS-directed therapy. Collectively, our findings reveal a novel regulatory circuit governing RAS stability that is preferentially active in blood cancers and potentially druggable.

DOI: https://doi.org/10.64898/2026.01.07.698128

bioRxiv. 2026 Jan 05. pii: 2026.01.05.697729. [Epub ahead of print]

The E3 ubiquitin ligase mechanism specifying target-directed microRNA degradation.

Jakob Farnung, Elena Slobodyanyuk, Peter Y Wang, Lianne W Blodgett, Daniel H Lin, Susanne von Gronau, Brenda A Schulman, David P Bartel.

MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to form complexes that down-regulate target RNAs, including mRNAs from most human genes 1-3 . Within each complex, the miRNA pairs to target mRNAs to specify their repression, and AGO provides effector function while also protecting the miRNA from cellular nucleases 2-5 . Although much has been learned about this mode of posttranscriptional gene regulation, less is known about how the miRNAs themselves are regulated. In one such regulatory pathway, unusual miRNA targets called "trigger" RNAs reverse the canonical regulatory logic and instead down-regulate microRNAs 6-21 . This target- d irected m iRNA d egradation (TDMD) is thought to require a c ullin- R ING E3 ligase (CRL) because it depends on the cullin protein CUL3 and other ubiquitylation components, including the BC-box protein ZSWIM8 (ref. 22,23). ZSWIM8 is required for murine perinatal viability and for destabilization of most short-lived miRNAs, but is otherwise poorly understood 23-25 . Here, we demonstrate that a human AGO-miRNA- trigger complex selectively binds ZSWIM8 for CUL3-mediated polyubiquitylation of the AGO protein within this complex. Cryogenic electron-microscopy (cryo-EM) analyses show how ZSWIM8 recognizes the distinct AGO2 and miRNA-trigger conformations shaped by pairing of the miRNA to the trigger. For example, this pairing extracts the miRNA from a binding pocket within AGO2, allowing the pocket to be captured by ZSWIM8, and it directs the trigger RNA along a distinct trajectory to be also recognized by ZSWIM8. These results biochemically establish AGO binding and polyubiquitylation as the key regulatory step of TDMD, define a unique CRL class, and reveal generalizable RNA-RNA, RNA-protein, and protein-protein interactions that specify the ubiquitin-mediated degradation of AGO with exquisite selectivity. The substrate features recognized by the E3 ubiquitin ligase do not conform to a conventional degron 26-28 , but rather establish a two-RNA-factor authentication mechanism specifying a protein ubiquitylation substrate.

DOI: https://doi.org/10.64898/2026.01.05.697729

bioRxiv. 2026 Jan 08. pii: 2026.01.07.698237. [Epub ahead of print]

C. elegans E3 ubiquitin ligase EBAX-1 promotes non-apoptotic linker cell-type death through target-directed miRNA degradation.

Lauren B Horowitz, Olya Yarychkivska, Yun Lu, Shai Shaham.

Programmed cell death is essential for animal development and homeostasis, and its disruption accompanies many human disorders. Linker cell-type death (LCD) is a morphologically conserved non-apoptotic developmental cell death program with features resembling polyglutamine-dependent neurodegeneration. In C. elegans , LCD execution is mediated by ubiquitin proteasome system (UPS) components, but their proteolytic targets are unknown. Here we demonstrate that EBAX-1/ZSWIM8, a conserved E3 ligase, promotes C. elegans LCD by target directed miRNA degradation (TDMD). We show that EBAX-1 acts cell-autonomously as part of the UPS and requires its Cullin-2 binding motif to promote LCD. Loss of mir-35 family miRNAs, argonautes, or miRNA biogenesis factors, restores LCD to ebax-1 mutants. Furthermore, expression of viln-1 /villin mRNA, a predicted mir-35 target, is upregulated in dying cells and is required for LCD. Together, our studies suggest that TDMD mediated by EBAX-1 is important for the fidelity of non-apoptotic developmental cell death.

DOI: https://doi.org/10.64898/2026.01.07.698237