Structure and function analysis of Sam68 and <scp>hnRNP A1</scp> synergy in the exclusion of exon 7 from <scp><i>SMN2</i></scp> transcripts

Nadal, Marta; Antón, Rosa; Dorca-Arévalo, Jonatan; Estébanez‐Perpiñá, Eva; Tizzano, Eduardo F.; Fuentes‐Prior, Pablo

doi:10.1002/pro.4553

Cited by 3 publications

(2 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This TH -induced destabilization is likely due to the disruption of Sam68 interactions with other proteins. Indeed, Sam68 is known to interact with RNA-binding proteins like ILF3 and HNRNPA1, − and these interactions could be modulated and displaced by TH binding.…”

Section: Discussionmentioning

confidence: 99%

Stability-Based Proteomics for Investigation of Structured RNA–Protein Interactions

Bailey,

Martyr,

Hargrove

et al. 2024

Anal. Chem.

View full text Add to dashboard Cite

RNA−protein interactions are essential to RNA function throughout biology. Identifying the protein interactions associated with a specific RNA, however, is currently hindered by the need for RNA labeling or costly tiling-based approaches. Conventional strategies, which commonly rely on affinity pulldown approaches, are also skewed to the detection of high affinity interactions and frequently miss weaker interactions that may be biologically important. Reported here is the first adaptation of stability-based mass spectrometry methods for the global analysis of RNA−protein interactions. The stability of proteins from rates of oxidation (SPROX) and thermal protein profiling (TPP) methods are used to identify the protein targets of three RNA ligands, the MALAT1 triple helix (TH), a viral stem loop (SL), and an unstructured RNA (PolyU), in LNCaP nuclear lysate. The 315 protein hits with RNA-induced conformational and stability changes detected by TPP and/or SPROX were enriched in previously annotated RNA-binding proteins and included new proteins for hypothesis generation. Also demonstrated are the orthogonality of the SPROX and TPP approaches and the utility of the domain-specific information available with SPROX. This work establishes a novel platform for the global discovery and interrogation of RNA−protein interactions that is generalizable to numerous biological contexts and RNA targets.

show abstract

Section: Discussionmentioning

confidence: 99%

Stability-Based Proteomics for Investigation of Structured RNA–Protein Interactions

Bailey,

Martyr,

Hargrove

et al. 2024

Anal. Chem.

View full text Add to dashboard Cite

show abstract

“…KHDRBS1 has gained large attention by its abnormal expression in cancer, includes breast cancer and lung adenocarcinoma (24)(25)(26). Additionally, in neurobiology, the role of KHDRBS1 has been of interest, especially in neurodevelopment and neurodegenerative diseases (27,28). Collectively, KHDRBS1 is considered a promising therapeutic target in various diseases, but its role may vary among different diseases, especially in complex solid tumors.…”

Section: Introductionmentioning

confidence: 99%

KHDRBS1 as a novel prognostic signaling biomarker influencing hepatocellular carcinoma cell proliferation, migration, immune microenvironment, and drug sensitivity

Fan,

Liu,

Gong

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

BackgroundHuman tumors pose significant challenges, with targeted therapy against specific molecular targets or signaling pathways being a mainstay alongside surgical resection. Previous studies have implicated KHDRBS1 in the oncogenesis of certain human tumors such as colorectal and prostate cancers, underscoring its potential as a therapeutic target. However, the comprehensive expression pattern of KHDRBS1 in hepatocellular carcinoma (HCC) warrants further exploration.MethodsIntegrating and analyzing multi-omics, multi-cohort data from public databases, coupled with clinical samples and molecular biology validation, we elucidate the oncogenic role of KHDRBS1 in HCC progression. Additionally, leveraging HCC single-cell sequencing data, we segregate malignant cells into KHDRBS1-positive and negative subsets, uncovering significant differences in their expression profiles and functional roles.ResultsOur study identifies KHDRBS1 as a tumor-promoting factor in HCC, with its positivity correlating with tumor progression. Furthermore, we highlight the clinical significance of KHDRBS1-positive malignant cells, aiming to further propel its clinical utility.ConclusionKHDRBS1 plays a key role in HCC development. This study provides crucial insights for further investigation into KHDRBS1 as a therapeutic target in HCC.

show abstract

Structure and function analysis of Sam68 and hnRNP A1 synergy in the exclusion of exon 7 from SMN2 transcripts

et al. 2023

Self Cite

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the absence of a functional copy of the Survival of Motor Neuron 1 gene (SMN1). The nearly identical paralog, SMN2, cannot compensate for the loss of SMN1 because exon 7 is aberrantly skipped from most SMN2 transcripts, a process mediated by synergistic activities of Src‐associated during mitosis, 68 kDa (Sam68/KHDRBS1) and heterogeneous nuclear ribonucleoprotein (hnRNP) A1. This results in the production of a truncated, nonfunctional protein that is rapidly degraded. Here, we present several crystal structures of Sam68 RNA‐binding domain (RBD). Sam68‐RBD forms stable symmetric homodimers by antiparallel association of helices α3 from two monomers. However, the details of domain organization and the dimerization interface differ significantly from previously characterized homologs. We demonstrate that Sam68 and hnRNP A1 can simultaneously bind proximal motifs within the central region of SMN2 (ex7). Furthermore, we show that the RNA‐binding pockets of the two proteins are close to each other in their heterodimeric complex and identify contact residues using crosslinking‐mass spectrometry. We present a model of the ternary Sam68·SMN2 (ex7)·hnRNP A1 complex that reconciles all available information on SMN1/2 splicing. Our findings have important implications for the etiology of SMA and open new avenues for the design of novel therapeutics to treat splicing diseases.

show abstract

Structure and function analysis of Sam68 and hnRNP A1 synergy in the exclusion of exon 7 from SMN2 transcripts

Cited by 3 publications

References 70 publications

Stability-Based Proteomics for Investigation of Structured RNA–Protein Interactions

Stability-Based Proteomics for Investigation of Structured RNA–Protein Interactions

KHDRBS1 as a novel prognostic signaling biomarker influencing hepatocellular carcinoma cell proliferation, migration, immune microenvironment, and drug sensitivity

Structure and function analysis of Sam68 and hnRNP A1 synergy in the exclusion of exon 7 from SMN2 transcripts

Contact Info

Product

Resources

About