Biomedical subjects

Attila Reményi

Publications and source records attributed to Attila Reményi.

8 recordsLinked to original sources

PubMed2006

Docking interactions in protein kinase and phosphatase networks.

To achieve high biological specificity, protein kinases and phosphatases often recognize their targets through interactions that occur outside of the active site. Although the role of modular protein-protein interaction domains in kinase and phosphatase signaling has been well characterized, it is becoming clear that many kinases and phosphatases utilize docking interactions - recognition of a short peptide motif in target partners by a groove on the catalytic domain that is separate from the active site. Docking is particularly prevalent in serine/threonine kinases and phosphatases, and is a versatile organizational tool for building complex signaling networks; it confers a high degree of specificity and, in some cases, allosteric regulation.

Allosteric Regulation↗

PubMed2006

The Ste5 scaffold allosterically modulates signaling output of the yeast mating pathway.

Scaffold proteins organize signaling proteins into pathways and are often viewed as passive assembly platforms. We found that the Ste5 scaffold has a more active role in the yeast mating pathway: A fragment of Ste5 allosterically activated autophosphorylation of the mitogen-activated protein kinase Fus3. The resulting form of Fus3 is partially active-it is phosphorylated on only one of two key residues in the activation loop. Unexpectedly, at a systems level, autoactivated Fus3 appears to have a negative regulatory role, promoting Ste5 phosphorylation and a decrease in pathway transcriptional output. Thus, scaffolds not only direct basic pathway connectivity but can precisely tune quantitative pathway input-output properties.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits.

Living cells display complex signal processing behaviors, many of which are mediated by networks of proteins specialized for signal transduction. Here we focus on the question of how the remarkably diverse array of eukaryotic signaling circuits may have evolved. Many of the mechanisms that connect signaling proteins into networks are highly modular: The core catalytic activity of a signaling protein is physically and functionally separable from molecular domains or motifs that determine its linkage to both inputs and outputs. This high degree of modularity may make these systems more evolvable-in principle, novel circuits, and therefore highly innovative regulatory behaviors, can arise from relatively simple genetic events such as recombination, deletion, or insertion. In support of this hypothesis, recent studies show that such modular systems can be exploited to engineer nonnatural signaling proteins and pathways with novel behavior.

Animals↗

PubMed2005

The role of docking interactions in mediating signaling input, output, and discrimination in the yeast MAPK network.

Cells use a network of mitogen-activated protein kinases (MAPKs) to coordinate responses to diverse extracellular signals. Here, we examine the role of docking interactions in determining connectivity of the yeast MAPKs Fus3 and Kss1. These closely related kinases are activated by the common upstream MAPK kinase Ste7 yet generate distinct output responses, mating and filamentous growth, respectively. We find that docking interactions are necessary for communication with the kinases and that they can encode subtle differences in pathway-specific input and output. The cell cycle arrest mediator Far1, a mating-specific substrate, has a docking motif that selectively binds Fus3. In contrast, the shared partner Ste7 has a promiscuous motif that binds both Fus3 and Kss1. Structural analysis reveals that Fus3 interacts with specific and promiscuous peptides in conformationally distinct modes. Induced fit recognition may allow docking peptides to achieve discrimination by exploiting subtle differences in kinase flexibility.

Amino Acid Sequence↗

PubMed2004

Combinatorial control of gene expression.

Revealing the molecular principles of eukaryotic transcription factor assembly on specific DNA sites is pivotal to understanding how genes are differentially expressed. By analyzing structures of transcription factor complexes bound to specific DNA elements we demonstrate how protein and DNA regulators manage gene expression in a combinatorial fashion.

Animals↗

PubMed2003

Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers.

Members of the POU and SOX transcription factor families exemplify the partnerships established between various transcriptional regulators during early embryonic development. Although functional cooperativity between key regulator proteins is pivotal for milestone decisions in mammalian development, little is known about the underlying molecular mechanisms. In this study, we focus on two transcription factors, Oct4 and Sox2, as their combination on DNA is considered to direct the establishment of the first three lineages in the mammalian embryo. Using experimental high-resolution structure determination, followed by model building and experimental validation, we found that Oct4 and Sox2 were able to dimerize onto DNA in distinct conformational arrangements. We demonstrate that the DNA enhancer region of their target genes is responsible for the correct spatial alignment of glue-like interaction domains on their surface. Interestingly, these surfaces frequently have redundant functions and are instrumental in recruiting various interacting protein partners.

Animals↗

PubMed2003

OBF1 enhances transcriptional potential of Oct1.

The POU transcription factors Oct1 and Oct2 bind to DNA in various monomer and dimer configurations. Depending on the DNA sequence to which they bind, the dimers are arranged in configurations that are either accessible (PORE sequence) or inaccessible (MORE sequence) to the B-cell-specific cofactor OBF1 (OcaB, Bob1). As shown previously, the MORE and related sequences (such as the heptamer/octamer motif) are found in immunoglobulin heavy chain promoters. Here we show that the expression of Osteopontin, which contains a PORE sequence in its enhancer region, depends on the presence of OBF1 in B cells. OBF1 alleviates DNA sequence requirements of the Oct1 dimer on PORE-related sequences in vitro. Furthermore, OBF1 stabilizes POU dimer-DNA interactions and overrides Oct1 interface mutations, which abolish PORE-mediated dimerization without OBF1. Our data indicate that the PORE-type Oct1 or Oct2 dimer, rather than the monomer, is the primary target of the cofactor OBF1. Based on our biochemical data, we propose a mode of OBF1-Oct1 dimer interaction, suggesting a novel arrangement of the subdomain connectivities.

B-Lymphocytes↗

PubMed2002

Differential activity by DNA-induced quarternary structures of POU transcription factors.

Recent structural studies on transcription factors from the POU family in complex with multiple cognate DNA enhancer elements have established a novel concept in DNA-mediated formation of distinct conformations of transcription regulator assemblies. Two crystal structures of the Oct-1 transcription factor in the presence of two different DNA sites have demonstrated how its POU DNA-binding segment is capable in forming two unrelated dimer arrangements, which is DNA motif dependent. While one arrangement allows binding of the Oct-1 specific coactivator OBF-1, binding of this coactivator is blocked in the second arrangement because the binding site is involved in its own dimer assembly. Conversely, two crystal structures of another POU transcription factor, Pit-1, have demonstrated how the same overall assembly is maintained in the presence of two different DNA response elements. However, since the distance of the two Pit-1 half-binding sites on these elements differ by two base pairs, the overall dimensions of the two complexes vary, allowing binding of a specific represssor (N-CoR) in one conformation but not in the other. Thus, despite the occurrence of different DNA-mediated molecular mechanisms, the net result, conformation-dependent binding of further regulators, is equivalent. These data introduce a concept where the DNA motif not only serves as binding site for specific transcription factors but also regulates their function by mediating specific transcription factor assemblies, which determine binding to conformation-dependent coregulators.

Animals↗