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Molecular chaperones as specialized protein quality control enzymes form the core of cellular protein homeostasis. How chaperones selectively interact with their substrate proteins thus allocate their overall limited capacity remains poorly understood. Here, I present an integrated analysis of sequence and structural determinants that define interactions of protein domains as the basic protein folding unit with the Saccharomyces cerevisiae Hsp70 Ssb. Structural homologs of single-domain proteins that differentially interact with Ssb for de novo folding were found to systematically differ in complexity of their folding landscapes, selective use of nonoptimal codons, and presence of short discriminative sequences, thus highlighting pervasive trade-offs in chaperone-assisted protein folding landscapes. However, short discriminative sequences were found to contribute by far the strongest signal toward explaining Ssb interactions. This observation suggested that some chaperone interactions may be directly programmed in the amino acid sequences rather than responding to folding challenges, possibly for regulatory advantages.
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http://dx.doi.org/10.1016/j.str.2020.09.009 | DOI Listing |
Blood
March 2025
UC San Diego, La Jolla, California, United States.
Inherited bone marrow failure syndromes (IBMFS) are genetic disorders of impaired hematopoiesis that manifest in childhood with both cytopenias and extra-hematologic findings. While several IBMFS are categorized as ribosomopathies due to shared underlying ribosomal dysfunction, there is a broader disruption of the protein homeostasis (proteostasis) network across both classic and emerging IBMFS. Precise regulation of the proteostasis network, including mechanisms of protein synthesis, folding, trafficking, and degradation as well as associated stress response pathways, has emerged as essential for maintaining hematopoietic stem cell (HSC) function, providing new potential mechanistic insights into IBMFS pathogenesis.
View Article and Find Full Text PDFEur J Pharmacol
March 2025
Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia. Electronic address:
The endoplasmic reticulum (ER) plays a fundamental role in maintaining cellular homeostasis by ensuring proper protein folding, lipid metabolism, and calcium regulation. However, disruptions to ER function, known as ER stress, activate the unfolded protein response (UPR) to restore balance. Chronic or unresolved ER stress contributes to metabolic dysfunctions, including insulin resistance, non-alcoholic fatty liver disease (NAFLD), and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease.
View Article and Find Full Text PDFBiochim Biophys Acta Bioenerg
March 2025
Laboratory of Biophysics, Wageningen University and Research, 6708 WE Wageningen, the Netherlands. Electronic address:
The thylakoid membrane is the site of the light-dependent reactions of photosynthesis. It is a continuous membrane, folded into grana stacks and the interconnecting stroma lamellae. The CURVATURE THYLAKOID1 (CURT1) protein family is involved in the folding of the membrane into the grana stacks.
View Article and Find Full Text PDFJ Mol Biol
March 2025
Department of Chemistry and Biochemistry University of California, Los Angeles Los Angeles, CA 90095-1569.
I am Distinguished Professor in the Chemistry and Biochemistry Department at University of California, Los Angeles, where I was hired in 1985 as the first female assistant professor in the department. I received my PhD from University of California, San Diego, under the guidance of Professor David Kearns, where I used NMR spectroscopy to study drug binding to random sequence DNA and published the first two-dimensional NMR spectra of short synthetic DNA duplexes. From 1982-1985 I was a Damon Runyon-Walter Winchell Postdoctoral fellow in the Professor Alexander Rich laboratory, where I investigated structures of Z-DNA by NMR.
View Article and Find Full Text PDFSyst Biol Reprod Med
December 2025
Department of Molecular Endocrinology, ICMR- National Institute for Research in Reproductive and Child Health, Parel, Mumbai, India.
Polycystic ovary syndrome (PCOS) is a complex polygenic endocrinopathy affecting 5-20% of reproductive-age women. Familial studies, candidate gene studies, and GWAS have identified multiple PCOS-associated genetic loci. This study aims to identify the functional variants associated with PCOS.
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