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Protein phosphorylation provides molecular control of complex physiological events within cells. In many cases, phosphorylation on specific amino acids directly controls the assembly of multi-protein complexes by recruiting phospho-specific binding modules. Here, the function, structure, and cell biology of phosphotyrosine-binding domains is discussed.
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http://dx.doi.org/10.1038/nrm759 | DOI Listing |
Int J Biol Macromol
September 2025
Shaanxi Key Laboratory of Natural Products and Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Xianyang, China. Electronic address:
Pancreatic adenocarcinoma (PAAD) lacks effective therapies due to complex macromolecular signaling networks. Here, we identified the natural compound Trienomycin A (TA) as a potent binder and degrader of the key signaling adaptor protein Insulin Receptor Substrate 1 (IRS1), disrupting its macromolecular assembly in insulin-like growth pathways. Through integrated biochemical, cellular, and in vivo analyses, we demonstrated that TA directly bound the phosphotyrosine-binding (PTB) domain of IRS1, inducing proteasomal degradation of this critical macromolecular hub mediated by the E3 ubiquitin ligase FBXW8.
View Article and Find Full Text PDFActa Physiol (Oxf)
September 2025
Department of Molecular Medicine, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Aim: Tendons are fibrous tissues connecting muscles to bones, providing joint stability and enabling movement. Adaptor proteins regulate cellular processes essential for maintaining tendon function. Phosphotyrosine-binding domain-containing engulfment adaptor protein 1 (GULP1) participates in multiple cellular activities; however, its specific role in tendons remains unclear.
View Article and Find Full Text PDFJ Neurosci
July 2025
Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York 10962
Endosomal system dysfunction within neurons is a prominent early feature of Alzheimer's disease (AD) pathology. Multiple AD risk factors are regulators of endocytosis and known to cause hyperactivity of the early endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption and cholinergic neurodegeneration. Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine binding domain, Leucine zipper motif (APPL1), an important rab5 effector protein and signaling molecule has been shown in vitro to interface between endosomal and neuronal dysfunction through a rab5-activating interaction with the BACE1-generated C-terminal fragment of amyloid precursor protein (APP-βCTF), a pathogenic APP fragment generated within endosomal compartments.
View Article and Find Full Text PDFInt J Biol Macromol
May 2025
Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, 00185 Rome, Italy. Electronic address:
Protein-protein interaction domains are essential for cellular homeostasis and the regulation of various molecular pathways, mediating highly specific and reversible binding events. The PhosphoTyrosine-Binding domains (PTB) play a pivotal role in regulating several cellular events, by recognizing phosphorylated and, in some cases, non-phosphorylated ligands. In this study we investigated the folding and functional properties of the PTB domain of FRS2 (Fibroblast growth factor receptor substrate 2) under oxidative and reductive experimental conditions.
View Article and Find Full Text PDFMol Oncol
March 2025
Department of Molecular and Cellular Biology, University of Guelph, Canada.
Triple-negative breast cancer (TNBC) is highly metastatic and presents clinical challenges given the lack of targeted therapies. Here, we report that the ShcD phosphotyrosine adaptor protein is upregulated in TNBC, and its expression correlates with overall reduced patient survival and decreased response to chemotherapy. In human breast cancer cells, we demonstrate that ShcD expression promotes cell invasion and reduces adhesion, and that these effects are abrogated by mutating the ShcD phosphotyrosine binding (PTB) domain.
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