Publications by authors named "Nicolas S Gonzalez-Foutel"
Article Synopsis
- Tumor suppressor p53 (TP53) mutations in cancer lead to loss of its protective function and potential gain of oncogenic traits, with mutant forms often stabilized in tumors.
- Researchers conducted CRISPR screens to identify factors that regulate the stability of wild-type and mutant p53, revealing that most regulators affect both, but some, like those for mutant p53 R337H, are specific to that mutant.
- The study highlights FBXO42 as a positive regulator for certain p53 mutants and C16orf72/HAPSTR1 as a negative regulator linked to increased levels in breast cancer, suggesting potential targets for cancer therapy focused on p53 stability.
Many proteins do not fold into a fixed three-dimensional structure, but rather function in a highly disordered state. These intrinsically disordered proteins pose a unique challenge to protein engineering and design: How can proteins be designed de novo if not by tailoring their structure? Here, we will review the nascent field of design of intrinsically disordered proteins with focus on applications in biotechnology and medicine. The design goals should not necessarily be the same as for de novo design of folded proteins as disordered proteins have unique functional strengths and limitations.
View Article and Find Full Text PDFInsulin formulations with diverse oligomerization states are the hallmark of interventions for the treatment of diabetes. Here using single-molecule recordings we firstly reveal that insulin oligomerization can operate via monomeric additions and secondly quantify the existence, abundance and kinetic characterization of diverse insulin assembly and disassembly pathways involving addition of monomeric, dimeric or tetrameric insulin species. We propose and experimentally validate a model where the insulin self-assembly pathway is rerouted, favoring monomeric or oligomeric assembly, by solution concentration, additives and formulations.
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- - The study investigates how disordered proteins, like the adenovirus E1A protein, maintain their essential functions despite having diverse sequences, focusing on the mechanism of functional selection.
- - E1A competes with host factors to bind the retinoblastoma (Rb) protein, affecting cell cycle regulation, and this interaction is driven by specific binding motifs linked by a disordered region that ensures strong binding affinity.
- - The authors introduce the concept of "conformational buffering," which describes how changes in amino acid composition and sequence length help maintain effective binding across various E1A linkers, indicating a broader principle applicable to many disordered proteins.
Many kinases use reversible docking interactions to augment the specificity of their catalytic domains. Such docking interactions are often structurally independent of the catalytic domain, which allow for a flexible combination of modules in evolution and in bioengineering. The affinity of docking interactions spans several orders of magnitude.
View Article and Find Full Text PDFThe Database of Protein Disorder (DisProt, URL: https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website.
View Article and Find Full Text PDFPocket proteins retinoblastoma (pRb), p107 and p130 are negative regulators of cellular proliferation and multifunctional proteins regulating development, differentiation and chromatin structure. The retinoblastoma protein is a potent tumor suppressor mutated in a wide range of human cancers, and oncogenic viruses often interfere with cell cycle regulation by inactivating pRb. The LxCxE and pRb AB groove short linear motifs (SLiMs) are key to many pocket protein mediated interactions including host and viral partners.
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