Thirty years of structural changesMusacchio, Andrea
doi: 10.1038/s41594-023-01193-3pmid: 38191919
The concluding statement of Watson and Crick’s historic paper on the structure of DNA1 enshrines a key tenet of molecular mechanistic cell biology: “… the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material”. Function — heredity in this case — is embedded in the redundant sequence information of the two strands of DNA. Although not always expressed as blatantly, the intimate dependence of cellular function on the mechanical level of macromolecules is inspirational. The devil is in the structural detail, and the painstaking quest for the correct details and their returns in the form of reliable knowledge knows no shortcuts.
Communities in structural biologyWinn, Martyn David
doi: 10.1038/s41594-023-01197-zpmid: 38253661
Collaboration is key to modern science, with major advances using multiple complementary approaches and dependent on sophisticated infrastructure. Yet science is also highly personal, as each person carves out a reputation and career. How does this work out in reality, and how can communities be built to benefit science and scientists?
Keep quiet: the HUSH complex in transcriptional silencing and diseaseMüller, Iris; Helin, Kristian
doi: 10.1038/s41594-023-01173-7pmid: 38216658
The human silencing hub (HUSH) complex is an epigenetic repressor complex whose role has emerged as an important guardian of genome integrity. It protects the genome from exogenous DNA invasion and regulates endogenous retroelements by recruiting histone methyltransferases catalyzing histone 3 lysine 9 trimethylation (H3K9me3) and additional proteins involved in chromatin compaction. In particular, its regulation of transcriptionally active LINE1 retroelements, by binding to and neutralizing LINE1 transcripts, has been well characterized. HUSH is required for mouse embryogenesis and is associated with disease, in particular cancer. Here we provide insights into the structural and biochemical features of the HUSH complex. Furthermore, we discuss the molecular mechanisms by which the HUSH complex is recruited to specific genomic regions and how it silences transcription. Finally, we discuss the role of HUSH complex members in mammalian development, antiretroviral immunity, and diseases such as cancer.
Mechanical disengagement of the cohesin ringRicheldi, Martina; Pobegalov, Georgii; Higashi, Torahiko L.; Gmurczyk, Karolina; Uhlmann, Frank; Molodtsov, Maxim I.
doi: 10.1038/s41594-023-01122-4pmid: 37872232
Cohesin forms a proteinaceous ring that is thought to link sister chromatids by entrapping DNA and counteracting the forces generated by the mitotic spindle. Whether individual cohesins encircle both sister DNAs and how cohesin opposes spindle-generated forces remains unknown. Here we perform force measurements on individual yeast cohesin complexes either bound to DNA or holding together two DNAs. By covalently closing the hinge and Smc3Psm3–kleisin interfaces we find that the mechanical stability of the cohesin ring entrapping DNA is determined by the hinge domain. Forces of ~20 pN disengage cohesin at the hinge and release DNA, indicating that ~40 cohesin molecules are sufficient to counteract known spindle forces. Our findings provide a mechanical framework for understanding how cohesin interacts with sister chromatids and opposes the spindle-generated tension during mitosis, with implications for other force-generating chromosomal processes including transcription and DNA replication.
EMC rectifies the topology of multipass membrane proteinsWu, Haoxi; Smalinskaitė, Luka; Hegde, Ramanujan S.
doi: 10.1038/s41594-023-01120-6pmid: 37957425
Most eukaryotic multipass membrane proteins are inserted into the membrane of the endoplasmic reticulum. Their transmembrane domains (TMDs) are thought to be inserted co-translationally as they emerge from a membrane-bound ribosome. Here we find that TMDs near the carboxyl terminus of mammalian multipass proteins are inserted post-translationally by the endoplasmic reticulum membrane protein complex (EMC). Site-specific crosslinking shows that the EMC’s cytosol-facing hydrophilic vestibule is adjacent to a pre-translocated C-terminal tail. EMC-mediated insertion is mostly agnostic to TMD hydrophobicity, favored for short uncharged C-tails and stimulated by a preceding unassembled TMD bundle. Thus, multipass membrane proteins can be released by the ribosome–translocon complex in an incompletely inserted state, requiring a separate EMC-mediated post-translational insertion step to rectify their topology, complete biogenesis and evade quality control. This sequential co-translational and post-translational mechanism may apply to ~250 diverse multipass proteins, including subunits of the pentameric ion channel family that are crucial for neurotransmission.