All proteins are synthesized by the ribosome, a macromolecular complex that accomplishes the life-sustaining tasks of faithfully decoding mRNA and catalyzing peptide bond formation at the peptidyl transferase center (PTC). The ribosome has evolved an exit tunnel to host the elongating new peptide, protect it from proteolytic digestion, and guide its emergence. It is here that the nascent chain begins to fold. This folding process depends on the rate of translation at the PTC. We report here that besides PTC events, translation kinetics depend on steric constraints on nascent peptide side chains and that confined movements of cramped side chains within and through the tunnel fine-tune elongation rates.
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http://dx.doi.org/10.1016/j.jmb.2017.04.019 | DOI Listing |
Rev Physiol Biochem Pharmacol
January 2025
Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK.
Ribosomes use multiple electrical forces to regulate new protein construction, to ensure efficient protein cotranslation, chaperoning, and folding. When these electrical regulatory forces are disrupted as in point charge mutations, specific disease occurs from aberrantly folded proteins. α1 antitrypsin deficiency is perhaps the best-known misfolded protein disease and is covered in some detail.
View Article and Find Full Text PDFChem Rev
January 2025
Department of Chemistry, Stanford University, Stanford, California 94305, United States.
The nascent field of targeted protein degradation (TPD) could revolutionize biomedicine due to the ability of degrader molecules to selectively modulate disease-relevant proteins. A key limitation to the broad application of TPD is its dependence on small-molecule ligands to target proteins of interest. This leaves unstructured proteins or those lacking defined cavities for small-molecule binding out of the scope of many TPD technologies.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Department of Chemistry, University of California, Berkeley, CA 94720.
Copper is an essential nutrient for sustaining vital cellular processes spanning respiration, metabolism, and proliferation. However, loss of copper homeostasis, particularly misregulation of loosely bound copper ions which are defined as the labile copper pool, occurs in major diseases such as cancer, where tumor growth and metastasis have a heightened requirement for this metal. To help decipher the role of copper in the etiology of cancer, we report a histochemical activity-based sensing approach that enables systematic, high-throughput profiling of labile copper status across many cell lines in parallel.
View Article and Find Full Text PDFBio Protoc
January 2025
Glycometabolic Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Riken, 2-1 Hirosawa, Wako Saitama, Japan.
Cytosolic peptide:-glycanase (PNGase/NGLY1 in mammals), an amidase classified under EC:3.5.1.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
Class I major histocompatibility complex (MHC-I) proteins play a pivotal role in adaptive immunity by displaying epitopic peptides to CD8+ T cells. The chaperones tapasin and TAPBPR promote the selection of immunogenic antigens from a large pool of intracellular peptides. Interactions of chaperoned MHC-I molecules with incoming peptides are transient in nature, and as a result, the precise antigen proofreading mechanism remains elusive.
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