closed conformations. The ubiquitin molecules in open-conformation chains do not interact with each other, except for the covalent isopeptide bonds linking them together. In contrast, the closed conformation chains have interfaces with interacting residues. Altering the chain conformations exposes and conceals different parts of the ubiquitin protein, and the different linkages are recognized by proteins that are specific for the unique topologies that are intrinsic to the linkage. Proteins can specifically bind to ubiquitin via ubiquitin-binding domains (UBDs). The distances between individual ubiquitin units in chains differ between lysine 63- and 48-linked chains. The UBDs exploit this by having small spacers between ubiquitin-interacting motifs that bind lysine 48-linked chains (compact ubiquitin chains) and larger spacers for lysine 63-linked chains. The machinery involved in recognising polyubiquitin chains can also differentiate between K63-linked chains and M1-linked chains, demonstrated by the fact that the latter can induce proteasomal degradation of the substrate. Function The ubiquitination system functions in a wide variety of cellular processes, including: Antigen processing Apoptosis Biogenesis of organelles Cell cycle and division DNA transcription and repair Differentiation and development Immune response and inflammation Neural and muscular degeneration Maintenance of pluripotency Morphogenesis of neural networks Modulation of cell surface receptors, ion channels and the secretory pathway Response to stress and extracellular modulators Ribosome biogenesis Viral infection Membrane proteins Multi-monoubiquitination can mark transmembrane proteins (for example, receptors) for removal from membranes (internalisation) and fulfil several signalling roles within the cell. When cell-surface transmembrane molecules are tagged with ubiquitin, the subcellular localization of the protein is altered, often targeting the protein for destruction in lysosomes. This serves as a negative feedback mechanism, because often the stimulation of receptors by ligands increases their rate of ubiquitination and internalisation. Like monoubiquitination, lysine 63-linked polyubiquitin chains also has a role in the trafficking some membrane proteins. Genomic maintenance Proliferating cell nuclear antigen (PCNA) is a protein involved in DNA synthesis. Under normal physiological conditions PCNA is sumoylated (a similar post-translational modification to ubiquitination). When DNA is damaged by ultra-violet radiation or chemicals, the SUMO molecule that is attached to a lysine residue is replaced by ubiquitin. Monoubiquitinated PCNA recruits polymerases that can carry out DNA synthesis with damaged DNA; but this is very error-prone, possibly resulting in the synthesis of mutated DNA. Lysine 63-linked polyubiquitination of PCNA allows it to perform a less error-prone mutation bypass known by the template switching pathway. Ubiquitination of histone H2AX