Editorial [Hot Topic: Peripheral Proteins as Drug Targets (Guest Editor: Robert V. Stahelin) ]

More than half of all human proteins are located in (i.e. receptors and ion channels) or on (i.e. lipid-binding peripheral proteins) cellular membranes. These proteins function in cell signaling and membrane trafficking events to maintain cellular metabolism, growth, differentiation, and homeostasis. Thus, cellular membranes are a platform for intracellular communication where different extracellular signals regulate assembly of lipid-protein and protein-protein complexes. The metabolism of lipids by lipid phosphatases, kinases, phospholipases and more enzymes provides cellular membranes with a vast variety of lipid headgroups and acyl chains for spatial and temporal recruitment of peripheral proteins to specific membrane sites in cells. The interactions between lipids and target proteins are of generally high affinity and specificity and most often mediated by modular lipid-binding domains [1, 2]. These small domains (∼60-220 amino acids) have unique surface characteristics such as charge and hydrophobic moieties to dock onto different lipid membranes. These lipid-binding sites may serve as a ‘hot spot’ for drug development aimed at inhibiting protein function through abrogation of membrane binding. This is in contrast to the common target site of most enzyme inhibitors, the catalytic site, and may provide a more selective means of inhibiting or activating function of the lipid-dependent proteins. Recently, this concept was validated with in silico structure-based virtual ligand screening, which identified several lipid-binding inhibitors of a C2 domain [3]. Along with inhibition of lipid binding the different regions of cellular membranes (i.e. polar and nonpolar) represent target sites of potential therapeutic agents that could specifically disrupt or accentuate lipid-protein interactions within the bilayer [4]. The rapidly expanding field of interdisciplinary research surrounding biomembranes warrants a timely overview of lipid-dependent drug targets as well as strategies of targeting their inhibition and/or activation. Thus, this edition of Current Drug Targets is intended to bring together recent findings and novel concepts about peripheral proteins and their potential as drug targets. In the introductory article, the Stahelin lab provides an overview of the structure and function of lipid-protein interactions highlighting important peripheral protein drug targets and strategies of targeting both the peripheral proteins and membranes. The introductory article is followed by three reviews centering on the lipid second messenger diacylglycerol (DAG). DAG signals act as modulators of cell growth and apoptosis through interactions with a zinc finger DAG recognition motif known as the C1 domain. This is first addressed by Christine Gould and Alexandra Newton as they provide a wonderful overview of the DAG binding protein kinase C (PKC) family of proteins and their regulation by lipids, phosphorylation, scaffolding proteins and ubiquitin. They also describe current and future strategies of targeting PKCs and their regulatory proteins. Next, Fumio Sakane and colleagues highlight the mechanisms of diacylglycerol kinase (DGKs) regulation and their metabolism of DAG to phosphatidic acid. The authors discuss with keen insight the basis for DGKs as drug targets in diseases such as cancer, epilepsy, and autoimmune diseases. In the final installment of DAG signaling Peter Blumberg and colleagues present a seminal article on targeting the DAG binding C1 domain in drug development. Here the authors present the potential of the C1 domain as a drug target and draw attention to current therapeutics in clinical trials aimed at C1 domain targeting. Sphingolipids are a class of bioactive lipids that have received much attention in the last two decades as important regulators of cancer. In fact, enzymes associated with sphingolipid synthesis such as sphingosine kinase 1 (SK) [5] and ceramide kinase (CerK) [6] have been classified as peripheral proteins due to their ability to bind cellular membranes. Thus, three articles are included here to highlight the dynamic field of sphingolipids and some of the important drug targets involved in sphingolipid synthesis and/or degradation. In the first article, Yusuf Hannun, Youssef Zeidan and colleagues discuss the molecular targeting of acid ceramidase in cancer therapy. Acid ceramidase is a lipid hydrolase that is able to regulate ceramide and sphingosine-1- phosphate levels, traditionally two bioactive lipids in cancer among other diseases. Hannun, Zeidan and colleagues outline this enzyme from the gene to the protein in an astute and timely fashion. Next, Sarah Spiegel, Dai Shida and colleagues summarize SK and its role in cancer. The authors carefully and creatively address the properties of SK, its role in different types of cancers, and current inhibitor and clinical trial compounds of SK activity.