Volume 31 Issue 6, June 2024

The human cytoskeleton consists of three major classes of filaments: microfilaments, microtubules and intermediate filaments. Here, we summarize recent progress in deciphering the structure and function of intermediate filaments and their implications for human disease.

The molecular mechanisms that regulate the transition from totipotency into divergent cellular states are unclear. Two new studies show that the transcription factors TFAP2C, NR5A2 and TEAD4 (TNT) support the formation of a transient bipotent state by activating early pluripotency and trophectoderm genes and modulating HIPPO signaling.

The commander complex was recently shown through interactomic screens to be a ubiquitous and conserved protein complex with fundamental biological roles. Two recent reports together revealed the structure of the complete commander assembly and explored its functional implications.

Cryo-electron microscopy of brain tissue from two individuals with Down syndrome showed amyloid-β (Aβ) and tau filaments identical to those found in individuals with sporadic or dominantly inherited Alzheimer disease (AD), but also two types of Aβ₄₀ filaments with distinct structures different from those previously reported in AD and cerebral amyloid angiopathy.

During cell division, kinetochores anchor chromosomes to spindle microtubules. Here, the authors report a comprehensive structure–function analysis of the kinetochore’s main microtubule receptor, the KMN network, shedding new light on its organization.

Here, the authors determine the structure of the human outer kinetochore KMN network complex, showing that it forms an extended and rigid rod-like structure and that it exists in an auto-inhibited state which can be relieved by phosphorylation.

Researchers unveiled the structural details of sphingomyelin synthase (SMSr), shedding light on its role in sphingolipid biosynthesis. SMSr transfers the phosphoethanolamine from PE to ceramide, adding complexity to the field of lipid homeostasis.

Examining artificial embryos (gastruloids), Merle et al. uncover precise gene organization and proportional growth, providing insights into fundamental principles of developmental processes in mammalian systems.

Here, using cryo-EM, authors reveal that amyloid-β and tau are identical in Alzheimer disease and Down syndrome. This has implications for assessing whether adults with Down syndrome could be included in Alzheimer disease clinical trials.

The study presents a high-resolution structure of the retriever complex and a model of the retriever–CCC assembly, providing a mechanistic framework for studying how retriever facilitates endosomal recycling of diverse membrane proteins.

Here, the authors report the structure of the native Commander complex and reveal key interactors by mass spectrometry-based proteomics.

Using cryo-electron microscopy and integrative modeling, the authors defined the structure of vimentin intermediate filaments, revealing a helical tube built of five protofibrils that enclose a fiber of low-complexity N-terminal domains.

Here the authors report that TFAP2C and NR5A2, two TF lineage regulators, activate both inner cell mass and trophectoderm programs in totipotent mouse embryos, leading to ‘bipotency activation’ to initiate the first cell-fate specification.

Here the authors identify the transcription factors TFAP2C and TEAD4 as a bistable switch that reconciles into Hippo ON and OFF states, establishing a composite state at the eight-cell stage and critically regulating lineage diversification.

Here the authors leverage state-of-the-art quantitative proteomics to provide a comprehensive overview of the human citrullinome. Supporting evidence from peptide microarrays hints at the potential clinical relevance of some of the identified sites.