Complex organisms have evolved from a limited number of primordial genes and proteins. However, the mechanisms by which the earliest proteins evolved and then served as the origin for the present diversity of protein function are unknown. Here, we outline a hypothesis based on the 'new view' of proteins whereby one sequence can adopt multiple structures and functions. We suggest that such conformational diversity could increase the functional diversity of a limited repertoire of sequences and, thereby, facilitate the evolution of new proteins and functions from old ones.
We have identified a family of 'Agenet' domains that are plant-specific homologs of Tudor domains. This finding has been extended, using a combination of sequence- and structure-dependent approaches, to show that the three β-stranded core regions of Tudor, PWWP, chromatin-binding (Chromo) and MBT domains are homologous because they originate from a common ancestor. In addition, we have revealed pairs of tandem repeats in the fragile X mental retardation protein (FMRP) family that are also members of this Tudor domain 'Royal Family'.
It has been estimated that a large fraction of cellular proteins are natively disordered. Current opinion largely holds that natively disordered proteins are more 'adaptive', leading to advantages in regulation and in binding diverse ligands. Here, we argue for another, simple, physically based reason. Disordered proteins often have large intermolecular interfaces, the size of which is dictated by protein function. For proteins to be stable as monomers with extensive interfaces, protein size would need to be 2-3 times larger. This would either increase cellular crowding or enlarge the size of the cell by 15-30%, owing to the increase in the sequence length. Smaller sizes of cells, proteins, DNA and RNA conserve energy. Thus, disordered proteins provide a simple yet elegant solution to having large intermolecular interfaces, but with smaller protein, genome and cell sizes.
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.
CFEM, an eight cysteine-containing domain, has been identified by analyzing over 25 fungal sequences selected from database sequence searches. Features of CFEM suggest that it is a novel domain with characteristics distinct from known cysteine-rich domains. Some CFEM-containing proteins (e.g. Pth11 from Magnaporthe grisea) are proposed to have important roles in fungal pathogenesis.
Sec1/Munc-18 (SM) proteins are essential for intracellular membrane fusion reactions. Most of them bind to membrane-associated soluble N-ethylmaleimide-sensitive fusion (NSF)-attachment protein receptors (SNAREs) of the syntaxin subfamily but it is unclear whether regulating syntaxins is their primary role. Recent studies now have shown that the mechanism of syntaxin binding is not conserved, even though the structures of both protein families are. Amazing as this might be for those considering the evolution of conserved folds, it leaves the question of how SM proteins operate in membrane fusion unanswered.
G-protein-coupled receptors form homomers and heteromers; agonist-induced conformational changes within interacting receptors of the oligomer modify their pharmacology, signalling and/or trafficking. When these receptors are activated, the oligomers rearrange and cluster and a novel mechanism of receptor-operation regulation by oligomer intercommunication is possible. This intercommunication would be assisted by components of the plasma membrane and by scaffolding proteins. Receptor cross-sensitization, cross-desensitization and novel, integrated receptor responses can then develop between oligomeric receptor complexes of the cluster without direct contact between them. This concept gives a new perspective to the understanding of neurotransmission and neuronal plasticity.
Many experiments could be improved with better experimental design and statistical analysis. Badly designed experiments can lead to incorrect conclusions and wasted time and scientific resources. Such experiments are unethical if they involve animals or humans. Good experimental design requires clearly defined objectives and control of the major sources of variation. In this article, a small mouse experiment involving the response of a liver enzyme to the administration of an antioxidant is used to illustrate some important design concepts such as the control and partitioning of sources of variation using factorial and randomized block designs and the estimation of appropriate sample sizes. Scientists clearly need better training in experimental design with better access to consultant statisticians for more complex situations.
There are two major lines of thinking concerning the mechanisms responsible for specificity in receptor tyrosine kinase signalling. On one hand, receptors might provide instructive signals that dictate cell-fate decisions and, on the other, they might generate permissive signals unleashing responses that are inherently defined in the protein repertoire of target cells. Recent data indicate that the signalling activity of the Met receptor for hepatocyte growth factor is affected by association with cell-specific surface molecules, namely the α6β4 integrin, Plexin B1 and CD44. This suggests that integration of cell-restricted expression of receptor partners that modulate kinase outputs with the intrinsic signalling features of receptors is required for specification of biological responses.
Naturally occurring substances derived from plants currently have, and will continue to have, a relevant place in drug discovery. The medieval Persian physicians have provided long lists of plants that they used to treat cephalalgia. Some of these substances are employed in clinical practice today; however, still more of these naturally occurring substances could be of use in modern medicine.