Pharmacological interference with protein-protein interactions mediated by coiled-coil motifs.
Coiled coils are bundles of intertwined alpha-helices that provide protein-protein interaction sites for the dynamic assembly and disassembly of protein complexes. The coiled-coil motif combines structural versatility and adaptability with mechanical strength and specificity. Multimeric proteins that rely on coiled-coil interactions are structurally and functionally very diverse, ranging from simple homodimeric transcription factors to elaborate heteromultimeric scaffolding clusters. Several coiled-coil-bearing proteins are of outstanding pharmacological importance, most notably SNARE proteins involved in vesicular trafficking of neurotransmitters and viral fusion proteins. Together with their crucial roles in many physiological and pathological processes, the structural simplicity and reversible nature of coiled-coil associations render them a promising target for pharmacological interference, as successfully exemplified by botulinum toxins and viral fusion inhibitors. The alpha-helical coiled coil is a ubiquitous protein domain that mediates highly specific homo- and heteromeric protein-protein interactions among a wide range of proteins. The coiled-coil motif was first proposed by Crick on the basis of X-ray diffraction data on alpha-keratin more than 50 years ago (Crick 1952, 1953) and nowadays belongs to the best-characterized protein interaction modules. By definition, a coiled coil is an oligomeric protein assembly consisting of several right-handed amphipathic alpha-helices that wind around each other into a superhelix (or a supercoil) in which the hydrophobic surfaces of the constituent helices are in continuous contact, forming a hydrophobic core. Both homomeric and heteromeric coiled coils with different stoichiometries are possible, and the helices can be aligned in either a parallel or an antiparallel topology (Harbury et al. 1993, 1994). Stoichiometry and topology are governed by the primary structure, that is, the sequence of the polypeptide chains, and a given protein can participate in multiple assembly-disassembly equilibria among several coiled coils differing in stoichiometry and topology (Portwich et al. 2007). Protein complexes whose oligomeric quaternary structures - and, hence, biological activities - depend on coiled-coil interactions include transcription factors, tRNA synthetases (Biou et al. 1994; Cusack et al. 1990), cytoskeletal and signal-transduction proteins, enzyme complexes, proteins involved in vesicular trafficking, viral coat proteins, and membrane proteins (Langosch and Heringa 1998). It is thus not surprising that coiled-coil motifs have gained great attention as potential targets for modulating protein-protein interactions implicated in a large number of diseases. In this review, we will first discuss some fundamental functional and structural aspects of a simple and well-characterized representative of coiled-coil transcription factors (Sect. 1) before considering two more complex coiled coils found in scaffolding proteins involved in mitosis and meiosis and vesicular trafficking Sect. 2). This will set the stage for addressing the role of coiled coils in viral infection (Sect. 3) as well as strategies of interfering with such protein-protein interactions therapeutically (Sect. 4 and 5).
Strauss
H M
HM
Nanolytics, Gesellschaft für Kolloidanalytik mbH, Am Mühlenberg 11, Potsdam, Germany.
Keller
S
S
D020816:Amino Acid Motifs / Q000187:drug effects / Q000502:physiology*; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D016350:Leucine Zippers / Q000502:physiology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014777:Virus Diseases / Q000378:metabolism
D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C501391:GCN4 protein, S cerevisiae; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors