Mass Spec Roundup: Assembly, Adhesion and Aging…

Four of a Kind: Glucocorticoid Receptor Forms Tetramers to Regulate Genes

A study in Nucleic Acids Research has challenged long-held assumptions about how the glucocorticoid receptor (GR) assembles and activates gene regulation. Using a suite of structural and analytical tools – including X-ray crystallography, molecular dynamics simulations, mass spectrometry, and high-resolution fluorescence microscopy – researchers at the University of Barcelona have found that the GR forms tetrameric complexes rather than the monomers or dimers typical of other nuclear receptors.

“This is the first time that we present to the scientific community a coherent mechanism to explain how the GR associates within the cell nucleus,” said Eva Estébanez-Perpiñá, the study’s lead author. The work shows that the receptor’s ligand-binding domain drives its self-assembly, acting “as a kind of building block in a molecular LEGO to form more complex structures,” the authors write. These higher-order oligomers – mainly tetramers – represent the receptor’s active state when bound to DNA.

The team also found that mutations affecting the GR’s surface residues can disrupt multimerization and transcriptional activity, offering new insight into disorders such as Chrousos syndrome. According to the authors, the receptor behaves like a “molecular contortionist,” flexibly switching between open and closed conformations to coordinate gene expression.

“Ultimately, our research lays the foundation for the design of precision drugs capable of modulating GR function with unprecedented specificity.” 

Top-Down Proteomics Deciphers the Catenin Phospho-Code

By extending the reach of top-down proteomics, a new Angewandte Chemie International Edition study has revealed how mechanical stress fine-tunes phosphorylation within cell–cell adhesion proteins. Using individual ion mass spectrometry (I²MS), a research team at Northwestern University, led by Neil Kelleher, achieved isotopic resolution of intact β- and α-catenins – large 85–110 kDa proteins central to adherens junctions.

The team’s denatured I²MS and fragment-ion mode, I²MS², captured up to ten phosphorylation states on β-catenin and seven on α-catenin, resolving site-specific changes linked to actomyosin contractility. “Our results are consistent with a ‘catenin phospho-code’ model, wherein combinatorial phosphorylation patterns reflect and potentially modulate the mechanotransductive environment at cell–cell adhesions,” the authors write.

Complementary bottom-up LC–MS mapping identified mechano-sensitive residues such as β-catenin S552 and S675, and α-catenin sites in the P-linker region (S652–T658), while S641 emerged as a constitutively phosphorylated residue essential for complex formation.

According to the authors, “this work establishes top-down I²MS as a viable approach for probing complex post-translational modification landscapes in high-mass proteins” and underscores proteoforms – not individual PTMs – as “the functional units of cellular regulation.” Their findings suggest that the interplay of multiple phosphorylation sites may encode how mechanical tension governs junction stability.

Molecular Switch Found for Photosynthesis and Aging in Plants

Researchers at the Daegu Gyeongbuk Institute of Science and Technology (DGIST) have uncovered how plants decide when to begin aging – a process that redirects photosynthetic machinery into nutrients for the next generation. The study, published in Nature Plants, identifies a long non-coding RNA, dubbed chlorella RNA, as a molecular switch linking the nucleus to the chloroplasts that power plant metabolism.

Using genetic screening, single-molecule fluorescence imaging, and high-resolution mass spectrometry, the team traced chlorella RNA’s path from its transcription in the nucleus to its binding within chloroplasts. There, it associates with proteins of the plastid-encoded RNA polymerase (PEP) complex, modulating the transcription of chloroplast genes that sustain photosynthesis.

When plants age, expression of chlorella RNA falls – driven by the declining activity of the GOLDEN2-LIKE (GLK) transcription factor – triggering chloroplast degradation and leaf senescence. “This study holds huge academic significance as it suggests how long non-coding regulatory RNAs are spatiotemporally regulated in aging,” said Pyungok Lim, who led the work.

According to Lim, manipulating chlorella RNA levels “could increase the photosynthetic efficiency and productivity of crops by regulating the development and aging of plant leaves.”

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