0000000000651072
AUTHOR
Elisa M. Nurminen
Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone.
T-cell protein tyrosine phosphatase (TCPTP) is a ubiquitously expressed non-receptor protein tyrosine phosphatase. It is involved in the negative regulation of many cellular signaling pathways. Thus, activation of TCPTP could have important therapeutic applications in diseases such as cancer and inflammation. We have previously shown that the α-cytoplasmic tail of integrin α1β1 directly binds and activates TCPTP. In addition, we have identified in a large-scale high-throughput screen six small molecules that activate TCPTP. These small molecule activators include mitoxantrone and spermidine. In this study, we have investigated the molecular mechanism behind agonist-induced TCPTP activation.…
Synthesis, in vitro activity, and three-dimensional quantitative structure-activity relationship of novel hydrazine inhibitors of human vascular adhesion protein-1.
Vascular adhesion protein-1 (VAP-1) belongs to the semicarbazide-sensitive amine oxidases (SSAOs) that convert amines into aldehydes. SSAOs are distinct from the mammalian monoamine oxidases (MAOs), but their substrate specificities are partly overlapping. VAP-1 has been proposed as a target for anti-inflammatory drug therapy because of its role in leukocyte adhesion to endothelium. Here, we describe the synthesis and in vitro activities of novel series of VAP-1 selective inhibitors. In addition, the molecular dynamics simulations performed for VAP-1 reveal that the movements of Met211, Ser496, and especially Leu469 can enlarge the ligand-binding pocket, allowing larger ligands than those s…
Novel Hydrazine Molecules as Tools To Understand the Flexibility of Vascular Adhesion Protein-1 Ligand-Binding Site: Toward More Selective Inhibitors
Vascular adhesion protein-1 (VAP-1) belongs to a family of amine oxidases. It plays a role in leukocyte trafficking and in amine compound metabolism. VAP-1 is linked to various diseases, such as Alzheimer's disease, psoriasis, depression, diabetes, and obesity. Accordingly, selective inhibitors of VAP-1 could potentially be used to treat those diseases. In this study, eight novel VAP-1 hydrazine derivatives were synthesized and their VAP-1 and monoamine oxidase (MAO) inhibition ability was determined in vitro. MD simulations of VAP-1 with these new molecules reveal that the VAP-1 ligand-binding pocket is flexible and capable of fitting substantially larger ligands than was previously believ…
Cystic Fibrosis Transmembrane Conductance Regulator Interacts with Multiple Immunoglobulin Domains of Filamin A
Mutations of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) that impair its apical localization and function cause cystic fibrosis. A previous report has shown that filamin A (FLNa), an actin-cross-linking and -scaffolding protein, interacts directly with the cytoplasmic N terminus of CFTR and that this interaction is necessary for stability and confinement of the channel to apical membranes. Here, we report that the CFTR N terminus has sequence similarity to known FLNa-binding partner-binding sites. FLNa has 24 Ig (IgFLNa) repeats, and a CFTR peptide pulled down repeats 9, 12, 17, 19, 21, and 23, which share sequence similarity yet differ from the other FLN…
β2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding
AbstractLeukocyte integrins of the β2 family are essential for immune cell-cell adhesion. In activated cells, β2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the β2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization, and cell spreading. Thr758 is contained in a Thr triplet of β2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin, and 14-3-3 proteins to phosphorylated and unphosphorylated β2 integrins by biochemical methods and x-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (Kd, 261…