Cotranslational Pulling Forces Alter Outcomes of Protein Synthesis

As nascent proteins are synthesized by the ribosome, interactions between the nascent protein and its environment can create pulling forces that are transmitted to the ribosome's catalytic center. These forces can affect the rate and outcomes of translation. We use atomistic and coarse-grained simulation to characterize the origins of pulling forces, the propagation of force to catalytic center of the ribosome, and the effects of force on synthetic outcomes. We uncover a novel form of pulling force-mediated regulation in which the forces generated by the integration of a transmembrane helix induce frameshifting in a viral polyprotein. Computational force measurements of hundreds of mutant viral sequences in combination with deep mutational scanning experiments reveal the structural and sequence-level features that enable this powerful regulatory mechanism. Force measurements are also used to provide a molecular picture for complex pulling force experiments on multispanning membrane proteins. In particular, we identify signatures of cotranslational helix packing interactions and the translocation of surface helices. To understand how forces are propagated through the nascent protein in the ribosomal exit tunnel, we ran and analyzed hundreds of microseconds of atomistic molecular dynamics with an applied pulling force on the nascent protein. The simulations reveal how the secondary structure of nascent proteins and their interactions with the ribosome control force propagation. The inhibition of force transduction by nascent protein-ribosome interactions explains how amino acids tens of angstroms away from the catalytic center of the ribosome can still influence the force-induced restart of stalled ribosomes.</p

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead