Reviews & Analysis

The tumour suppressor breast and ovarian cancer type 1 susceptibility protein (BRCA1) is integral for the maintenance of genome stability through its roles in cell cycle checkpoint control and DNA repair. Recent studies have revealed the presence of BRCA1 complexes with distinct roles in the DNA damage response.

Formins are highly conserved proteins with essential roles in remodelling the actin and microtubule cytoskeletons. The emerging complexity in the mechanisms governing formin activity mirrors the wide range of essential functions that they perform in cell motility, cell division and cell and tissue morphogenesis.

The pH of individual cellular compartments is independently regulated and highly variable. Molecules that sense the proton concentration and dynamically transport acid and base equivalents stringently regulate pH to ensure that it is maintained at optimal levels for organellar function.

Branched structures are present at all levels of organization in living organisms. Recent studies suggest that cell competition and cell rearrangements might be conserved key features in branch formation that are controlled by local cell signalling events.

How integrins are trafficked by endocytosis markedly affects their distribution and function. Recent studies examining the molecular mechanisms of integrin trafficking show that it affects the recycling of key signalling receptors to influence cellular processes such as cytokinesis, cell migration and tumour angiogenesis.

A single type of dynein motor carries out all minus end-directed microtubule transport in the cytoplasm. Several multifunctional adaptors, including dynactin, LIS1, NUDE and NUDEL, Bicaudal D and RZZ, couple dynein to its wide range of cargos and regulate its function.

G protein-coupled receptors (GPCRs) mediate physiological responses to various hormones, neurotransmitters, sensory stimuli and other ligands. The signalling and trafficking properties of GPCRs are often fine-tuned by receptor-interacting proteins that are differentially expressed in distinct cell types.

Directed evolution optimizes protein function through successive generations of random mutation, artificial selection and screening. This design algorithm provides a reliable approach to engineering proteins with new and useful properties, and helps us to understand how natural evolution occurs.

The evolution of protein–protein interaction and metabolic networks is mostly based on the duplication and loss of entire genes or on point mutations, small insertions or deletions that affect gene regulation. However, network evolution can be understood only when spatiotemporal resolution is taken into account.

Ubiquitin-conjugating enzymes (E2s) are major regulators of ubiquitin chain assembly. These enzymes control ubiquitin chain initiation or elongation, the processivity of chain formation and the topology of the assembled chains.

How kinesin motors are regulated in cells to ensure the temporal and spatial fidelity of their microtubule-based activities is poorly understood. Recent work has revealed molecular mechanisms that control kinesin autoinhibition, activation, binding to cargos and microtubule tracks, and localization.

Non-muscle myosin II (NM II) is an actin-binding protein with actin cross-linking and contractile properties. The three mammalian NM II isoforms have both overlapping and distinct roles in cell adhesion and cell migration and their mutation results in specific developmental defects and disease phenotypes.

Kinesins are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs. The mechanisms by which kinesins recognize, bind and unload cargo, and also regulate processes such as higher brain function, tumour suppression and developmental patterning, are becoming clear.

Ubiquitin-binding domains (UBDs) are modular elements that bind non-covalently to the protein modifier ubiquitin. Recent structures of ubiquitin–UBD complexes at atomic-level resolution reveal some of the mechanisms that underlie the versatile functions of ubiquitinin vivo.

Alternative splicing is an important gene regulatory mechanism for generating proteomic diversity, which markedly affects human development and is misregulated in many human diseases. Alternative splicing can be regulated at different stages of spliceosome assembly and by different mechanisms.

Amino acid substitutions in divergent protein families reflect both Darwinian selection and neutral evolution. The latter operates within structural and functional constraints and arises from the need to conserve protein architecture and interactions that are important for the survival of the organism.

Protein denitrosylation, the removal of nitric oxide groups from Cys thiols, was once considered to be a spontaneous event. Now, the discovery of denitrosylases, the enzymes that catalyse this process, is advancing our understanding of redox-based signalling in normal and aberrant cellular functions.

Stem cell differentiation and the maintenance of self-renewal are intrinsically complex processes. They require the coordinated and dynamic expression of hundreds of genes and proteins, in precise response to external signalling cues. Systems biology approaches are helping to dissect this complexity.

Polycomb group (PcG) proteins constitute a conserved gene silencing system with widespread roles in multicellular development, stem cell biology and cancer. Recent studies suggest that PcG-mediated gene silencing may involve histone modifications and a possible block in transcriptional elongation.

It is now recognized that cell signalling and endocytic membrane trafficking are intimately and bidirectionally linked in animal cells. The mechanistic and functional principles that underlie the relationship between these cellular processes are becoming increasingly evident across many systems.