Lighting up Nobel Prize-winning studies with protein intrinsic disorder

Piersimoni, Lolita; Malek, Marina Abd el; Bhatia, Twinkle; Bender, Julian; Brankatschk, Christin; Sánchez, Jaime Calvo; Dayhoff, Guy W.; Ianni, Alessio Di; Parra, Jhonny Oscar Figueroa; Garcia-Martinez, Dailen; Hesselbarth, Julia; Köppen, Janett; Lauth, Luca M; Lippik, Laurin; Machner, Lisa; Sachan, Shubhra; Schmidt, L.D.; Selle, Robin; Skalidis, Ioannis; Sorokin, Oleksandr; Ubbiali, Daniele; Voigt, Bruno; Wedler, Alice; Wei, Alan An Jung; Zorn, Peter; Dunker, A. Keith; Köhn, Marcel; Sinz, Andrea; Uversky, Vladimir N.

doi:10.1007/s00018-022-04468-y

Cited by 10 publications

(3 citation statements)

References 259 publications

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“…This infers that the alternatively spliced exons that translate to a highly disordered protein region could have a large regulatory potential for focal adhesions ( Supplementary Figure S1B ). Intrinsically disordered proteins have gained substantial interest in the past few years; although they lack a stable tertiary structure, their unstructured segments confer a wide variety of biological functions ( Uversky et al., 2000 ; Dunker et al., 2001 ; Piersimoni et al., 2022 ). The N-terminus of canonical Pxn has been studied because it includes large and flexible IDRs between the short functional LD motifs, which mostly interact with FAK, Vcl, and Src proteins ( Brown et al., 2005 ; Hu et al., 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Rbfox1 controls alternative splicing of focal adhesion genes in cardiac muscle cells

Zorn,

Calvo Sánchez,

Alakhras

et al. 2024

Journal of Molecular Cell Biology

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Alternative splicing is one of the major cellular processes that determine the tissue-specific expression of protein variants. However, it remains challenging to identify physiologically relevant and tissue-selective proteins that are generated by alternative splicing. Hence, we investigated the target spectrum of the splicing factor Rbfox1 in the cardiac muscle context in more detail. By using a combination of in silico target prediction and in cell validation, we identified several focal adhesion proteins as alternative splicing targets of Rbfox1. We focused on the alternative splicing patterns of Vinculin (Metavinculin isoform) and Paxillin (extended Paxillin isoform) and identified both as potential Rbfox1 targets. Minigene analyses suggested that both isoforms are promoted by Rbfox1 due to binding in the introns. Focal adhesions play an important role in the cardiac muscle context, since they mainly influence cell shape, cytoskeletal organization, and cell–matrix association. Our data confirmed that depletion of Rbfox1 changed cardiomyoblast morphology, cytoskeletal organization, and multinuclearity after differentiation, which might be due to changes in alternative splicing of focal adhesion proteins. Hence, our results indicate that Rbfox1 promotes alternative splicing of focal adhesion genes in cardiac muscle cells, which might contribute to heart disease progression, where downregulation of Rbfox1 is frequently observed.

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Section: Discussionmentioning

confidence: 99%

Rbfox1 controls alternative splicing of focal adhesion genes in cardiac muscle cells

Zorn,

Calvo Sánchez,

Alakhras

et al. 2024

Journal of Molecular Cell Biology

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“…Even though Volodya left Indiana in 2010, we continue to collaborate [ 42 , 43 ]. Words cannot express how much Volodya has helped me and our students over our many years together.…”

Section: The Impact Of Vladimir Uversky On the Scientific Community A...mentioning

confidence: 99%

Per Aspera ad Chaos: Vladimir Uversky’s Odyssey through the Strange World of Intrinsically Disordered Proteins

et al. 2023

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“…It is one of the most studied and prominent representatives of intrinsically disordered proteins (IDPs) (5). The structural and functional characterization of IDPs has been recognized as a crucial task in structural biology, considering the abundance of proteins containing intrinsically disordered regions (IDRs) in all domains of life (archaea, bacteria, eukaryotes) and in viruses (6, 7). More than 40 years after the discovery of the prominent tumor suppressor protein the structure and spatial arrangement of the tetrameric p53 complex, remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Structural Assessment of the Full-Length Wild-Type Tumor Suppressor Protein p53 by Mass Spectrometry-Guided Computational Modeling

Ianni

Tüting

Kipping

et al. 2022

Preprint

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The tetrameric tumor suppressor p53 represents a great challenge for 3D-structural analysis due to its high degree of intrinsic disorder (ca. 40%). We aim to shed light on the structural and functional roles of p53's C-terminal region in full-length, wild-type human p53 tetramer and their importance for DNA binding. For this, we employed complementary techniques of structural mass spectrometry (MS) in an integrated approach with AI-based computational modeling. Our results show no major conformational differences in p53 between DNA-bound and DNA-free states, but reveal a substantial compaction of p53's C-terminal region. This supports the proposed mechanism of unspecific DNA binding to the C-terminal region of p53 prior to transcription initiation by specific DNA binding to the core domain of p53. The synergies between complementary structural MS techniques and computational modeling as pursued in our integrative approach is envisioned to serve as general strategy for studying intrinsically disordered proteins (IDPs) and intrinsically disordered region (IDRs).

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Lighting up Nobel Prize-winning studies with protein intrinsic disorder

Cited by 10 publications

References 259 publications

Rbfox1 controls alternative splicing of focal adhesion genes in cardiac muscle cells

Rbfox1 controls alternative splicing of focal adhesion genes in cardiac muscle cells

Per Aspera ad Chaos: Vladimir Uversky’s Odyssey through the Strange World of Intrinsically Disordered Proteins

Structural Assessment of the Full-Length Wild-Type Tumor Suppressor Protein p53 by Mass Spectrometry-Guided Computational Modeling

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