Advances in Protein Chemistry最新文献

DNA polymerases are molecular motors directing the synthesis of DNA from nucleotides. All polymerases have a common architectural framework consisting of three canonical subdomains termed the fingers, palm, and thumb subdomains. Kinetically, they cycle through various states corresponding to conformational transitions, which may or may not generate force. In this review, we present and discuss the kinetic, structural, and single-molecule works that have contributed to our understanding of DNA polymerase function.

Ionotropic glutamate receptors are the major excitatory neurotransmitters in mammalian brain but are found throughout the animal kingdom as well as in plants and bacteria. A great deal of progress in understanding the structure of these essential neurotransmitter receptors has been made since the first examples were cloned and sequenced in 1989. The atomic structure of the ligand-binding domain of several ionotropic glutamate receptors has been determined, and a great deal of progress has been made in relating the structural properties of the binding site to the function of the intact receptor. In addition, the identification of glutamate receptors from a wide variety of organisms ranging from several types of bacteria to Arabidopsis to a range of animal species has made glutamate receptors a molecular laboratory for studying the evolution of proteins. The fact that glutamate receptors are a particularly ancient intercellular signaling molecule suggests a potential role in the transition from single celled to multicellular organisms. This review focuses on the structure and dynamics of ionotropic glutamate receptors and their relation to the function and evolution of these proteins.

Chemotaxis is an important cellular response common in biology. In many chemotaxing cells the signal that regulates movement is initiated by G protein-coupled receptors on the cell surface that bind specific chemoattractants. These receptors share important structural similarities with other G protein-coupled receptors, including rhodopsin, which currently serves as the best starting point for modeling their structures. However, the chemotaxis receptors also share a number of relatively unique structural features that are less common in other GPCRs. The chemoattractant ligands of chemotaxis receptors exhibit a broad variety of sizes and chemical properties, ranging from small molecules and peptides to protein ligands. As a result, different chemotaxis receptors have evolved specialized mechanisms for the early steps of ligand binding and receptor activation. The mechanism of transmembrane signaling is currently under intensive study and several alternate mechanisms proposing different conformational rearrangements of the transmembrane helices have been proposed. Some chemotaxis receptors are proposed to form dimers, and in certain cases dimer formation is proposed to play a role in transmembrane signaling. In principle the structural and dynamical changes that occur during transmembrane signaling could be specialized for different receptors, or could be broadly conserved. Extensive mutagenesis studies have been carried out, and have begun to identify critical residues involved in ligand binding, receptor activation, and transmembrane signaling.

The pituitary hormones growth hormone (GH), prolactin (PRL) and placental lactogen (PL), are members of an extensive cytokine superfamily of hormones and receptors that share many of the same general structure-function relationships in expressing their biological activities. The biology of the pituitary hormones involves a very sophisticated interplay of cross-reactivity and specificity. Biological activity is triggered via a hormone-induced receptor homodimerization process that is regulated by tertiary features of the hormone. These hormones have an asymmetric four alpha-helical bundle structure that gives rise to two receptor binding sites that have distinctly different topographies and electrostatic character. This feature plays an important role in the regulation of these systems by producing binding surfaces with dramatically different binding affinities to the receptor extracellular domains (ECD). As a consequence, the signaling complexes for systems that activate through receptor homodimerization are formed in a controlled sequential step-wise manner. Extensive biochemical and biophysical characterization of the two hormone-receptor interfaces indicate that the energetic properties of the two binding sites are fundamentally different and that the receptor shows extraordinary conformational plasticity to mate with the topographically dissimilar sites on the hormone. An unexpected finding has been that the two hormone binding sites are allosterically coupled; a certain set of mutations in the higher affinity site can produce both conformational and energetic effects in the lower affinity site. These effects are so large that at some level they must have played some role in the evolution of the molecule.

The tumor necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins that are structurally related in their extracellular domains and specifically activated by the corresponding superfamily of TNF-like ligands. Members of this receptor superfamily are widely distributed and play important roles in many crucial biological processes such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis. A remarkable dichotomy of the TNFR superfamily is the ability of these receptors to induce the opposing effects of gene transcription for cell survival, proliferation, and differentiation and of apoptotic cell death. The intracellular signaling proteins known as TNF receptor associated factors (TRAFs) are the major signal transducers for the cell survival effects, while the death-domain-containing proteins mediate cell death induction. This review summarizes recent structural, biochemical, and functional studies of these signal transducers and proposes the molecular mechanisms of the intracellular signal transduction.

The vast majority of cytokine signaling is mediated by "shared" receptors that form central signaling components of higher-order complexes incorporating ligand-specific receptors. These include the common gamma chain (gamma(c)), common beta chain (beta(c)), and gp130, as well as others. These receptors have the dual tasks of cross-reactive cytokine recognition, and formation of precisely oriented multimeric signaling assemblies. Currently, detailed structural information on a shared receptor complex exists only for gp130, which is a highly pleiotropic shared cytokine signaling receptor essential for mammalian cell growth and homeostasis. To date, more than 10 different four-helix bundle ligands have been identified that incorporate gp130, or one of its close relatives such as LIF receptor, into functional oligomeric signaling complexes. In this review we summarize our current knowledge of shared receptor recognition and activation, with a focus on gp130. We discuss recent structural and functional information to analyze overall architectural assemblies of gp130 cytokine complexes and probe the basis for the extreme cross-reactivity of gp130 for its multiple cytokine ligands.