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The transcription factor and tumour suppressor p53 and its two homologues p63 and p73 form a family of proteins. p63 and p73 show much greater molecular complexity than p53 because they are expressed both as multiple alternatively spliced C-terminal isoforms, and as N-terminally deleted, dominant-negative proteins that show reciprocal functional regulation. In addition, several other factors, such as post-translational modifications and specific and common family regulatory proteins, result overall in subtle modulation of their biological effects. Although all p53, p63 and p73 family members are regulators of the cell cycle and apoptosis, the developmental abnormalities of p73- and p63-null mice do not show enhanced tumour susceptibility of p53 knockouts, suggesting that complex regulatory processes modulate the functional effects of this family of proteins.

POTRA (for polypeptide-transport-associated domain) is a novel domain identified in proteins of the ShlB, Toc75, D15 and FtsQ/DivlB families. In most cases, the POTRA domain is associated with a [beta]-barrel outer membrane domain and its function has been experimentally related to polypeptide transport in Toc75 (Tic-Toc protein import system in chloroplast) and ShlB families. In addition to potential key roles in protein transport across the outer membrane and in bacterial septation, the POTRA domain has attractive features for vaccine development in diseases such as cholera, meningitis, gonorrhoea and syphilis.

A striking property of speech perception is its resilience in the face of acoustic variability (among speech sounds produced by different speakers at different times, for example). The robustness of speech perception might, in part, result from multiple, complementary representations of the input, which operate in both acoustic--phonetic feature-based and articulatory--gestural domains. Recent studies of the anatomical and functional organization of the non-human primate auditory cortical system point to multiple, parallel, hierarchically organized processing pathways that involve the temporal, parietal and frontal cortices. Functional neuroimaging evidence indicates that a similar organization might underlie speech perception in humans. These parallel, hierarchical processing `streams', both within and across hemispheres, might operate on distinguishable, complementary types of representations and subserve complementary types of processing. Two long-opposing views of speech perception have posited a basis either in acoustic feature processing or in gestural motor processing; the view put forward here might help reconcile these positions.

The molecular structures of the infectious agents that cause transmissible spongiform encephalopathy (TSE) diseases are still not known despite the current wide acceptance of the prion hypothesis as the basis for their resolution. Here, data supporting and challenging the prion hypothesis in relation to both the biochemical and biological properties of TSE infectious agents are discussed. The need for the independent transmission of TSE agent-specific genetic information is described and the requirements for the molecule to carry this information are proposed. Such a molecule is likely to be a small nucleic acid encoding information to determine the diversity of the pathogenesis of TSE agents.

The nuclear transport field has completed a decade of fast-paced research dominated by the discovery of transport signals, receptors, and regulators. What might be considered the Holy Grail of nuclear transport--the physical basis of translocation through the nuclear pore--is now under close scrutiny. Recent publications describe structural and biochemical approaches that help address key aspects of the translocation mechanism. These studies have led to the affinity gradient, Brownian affinity gate and selective phase models of translocation.

Aquaporin-1 (AQP1) is a member of the diverse major intrinsic protein family of water and solute channels. AQP1 is known as an osmotic water channel in kidney, brain, vascular system and other tissues, and recently has been demonstrated to function as a cation channel gated by cGMR Electrophysiology and binding assays implicate direct cGMP binding in the AQP1 C-terminus and sequence similarities with cyclic-nucleotide-gated channels support the idea that the AQP1 C-terminus mediates ion channel activation. In this article, new data show that the AQP1 C-terminus also exhibits homology, at key residues, with the substrate-selectivity subdomain of cyclic nucleotide phosphodiesterases. Distinct pathways for fluxes of water and ions in the tetrameric AQP1 channel indicate an intriguing multifunctional capacity. The physiological role of AQP1 in transmembrane signaling remains to be elucidated for these channels expressed in native tissues.

Proteins associated with membranes total approximately a third of all proteins in a typical eukaryotic cell. However, the analysis of interactions between membrane proteins is difficult because of the hydrophobic nature of these proteins, and conventional biochemical and genetic assays are often of limited use. We summarize here recent yeast-based interaction technologies that can be applied to membrane proteins.

A novel FAD-binding domain, BLUF, exemplified by the N-terminus of the AppA protein from Rhodobacter sphaeroides, is present in various proteins, primarily from Bacteria. The BLUF domain is involved in sensing blue-light (and possibly redox) using FAD and is similar to the flavin-binding PAS domains and cryptochromes. The predicted secondary structure reveals that the BLUF domain is a novel FAD-binding fold.

The development of three-dimensional maps of the modified nucleotides in the ribosomes of Escherichia coli and yeast has revealed that most (~95% in E. coli and 60% in yeast) occur in functionally important regions. These include the peptidyl transferase centre, the A, P and E sites of tRNA- and mRNA binding, the polypeptide exit tunnel, and sites of subunit-subunit interaction. The correlations suggest that many ribosome functions benefit from nucleotide modification.

A novel domain (the BRICHOS domain) of ~100 amino acids has been identified in several previously unrelated proteins that are linked to major diseases. These include BR[I.sub.2], which is related to familial British and Danish dementia (FBD and FDD); Chondromodulin-I (ChM-I), related to chondrosarcoma; CA11, related to stomach cancer; and surfactant protein C (SP-C), related to respiratory distress syndrome (RDS). In several of these, the conserved BRICHOS domain is located in the propeptide region that is removed after proteolytic processing. Experimental data suggest that the role of this domain could be related to the complex post-translational processing of these proteins.

The ability of protein molecules to fold into their highly structured functional states is one of the most remarkable evolutionary achievements of biology. In recent years, our understanding of the way in which this complex self-assembly process takes place has increased dramatically. Much of the reason for this advance has been the development of energy surfaces (landscapes), which allow the folding reaction to be described and visualized in a meaningful manner. Analysis of these surfaces, derived from the constructive interplay between theory and experiment, has led to the development of a unified mechanism for folding and a recognition of the underlying factors that control the rates and products of the folding process.

Electron microscopic (EM) tomography is providing important new insights into the internal organization of mitochondria. The standard baffle model for cristae structure, called into question years ago, has now clearly been shown to be inaccurate. Depending on source and conformational state, cristae can vary from simple tubular structures to more complex lamellar structures merging with the inner boundary membrane through tubular structures 28 nm in diameter. The structural information provided by EM tomography has important implications for mitochondrial bioenergetics, biogenesis and the role of mitochondria in apoptosis. The structural paradigm defined by EM tomography is helping in the design of new experimental approaches to mitochondrial function.

Retrovirus particles contain a small, basic protein, the nucleocapsid (NC) protein, that possesses 'nucleic acid chaperone' activity - that is, the NC protein can catalyze the rearrangement of a nucleic acid molecule into the conformation that has the maximal number of base pairs. The molecular mechanism that underlies this effect is not understood. Because the chaperone activity is apparently crucial during the infectious process, NC is a potential target for antiviral therapy.

It is commonly supposed that the contribution of a bond to protein or nucleic acid stability is equal to the in situ stability of the bond itself. This is not true for the noncovalent bonds that stabilize molecular folding. In general, a bonding interaction contributes a free energy increment to protein or nucleic acid stability that is larger, an enthalpy increment that is smaller, and entropy and heat capacity increments that are more positive than the corresponding bond parameter.

Sterile alpha motif (SAM) domains are known to exhibit diverse protein--protein interaction modes. They can form multiple self-association architectures and also bind to various non-SAM domain-containing proteins. Surprising new work adds a completely unanticipated function for some SAM domains--the ability to bind RNA. Such functional diversity within a homologous protein family presents a significant challenge for bioinformatic function assignment.

The control of signal transduction involves post-translational modification of proteins at key amino acids. Cysteine residues are important in the control of `redox' cell-signaling pathways, as thiol chemistry offers the possibility of modification by structurally diverse species, including those derived from oxidized lipids, peroxides or nitric oxide. An important and provocative study of the modification of thiols in the transcription factor OxyR recently extended this hypothesis. The findings offer the enticing possibility that the cell can distinguish between different degrees of oxidant and nitrosative exposure by modification at a single site on a signaling molecule.

This article discusses the structural and functional aspects of KCNE proteins involved in the biological transport of potassium ions. Results suggest that KCNE proteins are beta-subunits, consist of 103-153 amino acids, and influence gating of potassium channels.

The name HORMA domain, which is an abbreviation for Hop1p, Rev7p and MAD2, was suggested to denote the sequence conservation observed in DNA repair, chromosome synapsis and mitotic checkpoints. The different alignment of the HORMA domains demonstrated that a number of conserved motifs are incorporated. Moreover, two amino acid residues seemed constant. One is a glutamate residue located at the center of the domain, while the other is an arginine residue at the N-terminal region of the domain.

Biological membranes are composed of a complex mixture of lipids and proteins, and the membrane lipids support several key biophysical functions, in addition to their obvious structural role. Recent results from X-ray crystallography are shedding new light on the precise molecular details of the protein--lipid interface.

Ribonucleotide reductases (RNRs) catalyze the conversion of both purine and pyrimidine nucleotides to deoxynucleotides in all organisms and provide all the monomeric precursors essential for both DNA replication and repair. RNRs have been divided into three classes on the basis of their unique metallo-cofactors. The exquisitely controlled free radical chemistry used by all RNRs, and the commonality of the structures of the subunits where the nucleotide reduction process occurs, together provide compelling evidence for the importance of chemistry in the divergent evolution of RNRs from a common progenitor.

Recent work from Agarwala et al. has uncovered exquisite ventral patterning in the mesencephalon. Using electroporation in chicks, they show that ectopic expression of Sonic Hedgehog (Shh) in dorsal mesencephalon can recapitulate this patterning in its entirety. These results are discussed in the context of the purported role of Shh as a morphogen.

Bergmann glia in the cerebellum elaborately ensheathe Purkinje cell dendrites and synapses, and express high levels of [Ca.sup.2+]-permeable glutamate receptors (GluRs). Suppression of the [Ca.sup.2+] permeability by virus-mediated GluR2 transfer has revealed that GluR-mediated [Ca.sup.2+] signaling is essential to maintain both structural and functional connections between the glial cell and the glutamatergic synapses.