By Coiled Coil Motifs

Contents

1 Introduction: The GCN4 Leucine Zipper 462

1.1 Function 463

1.2 Structure 464

2 Coiled Coils in Scaffolding Proteins 467

2.1 The Ndc80 Complex 468

2.2 SNARE Proteins 469

3 Role of Coiled Coils in Viral Infection 471

3.1 Class I Fusion Proteins 472

3.2 Influenza Hemagglutinin 474

3.3 Gp41 of HIV-1 474

4 Therapeutic Interference with Coiled-Coil Interactions 475

4.1 Botulinum Toxins 475

4.2 Viral Fusion Inhibitors 476

5 Other Therapeutic Applications of Coiled Coils 477

References 478

Abstract Coiled coils are bundles of intertwined a-helices that provide proteinprotein 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

S. Keller

Leibniz Institute of Molecular Pharmacology FMP, Robert-Rossle-Str. 10, 13125 Berlin, Germany

[email protected]

E. Klussmann, J. Scott (eds.) Protein-Protein Interactions as New Drug Targets. 461

Handbook of Experimental Pharmacology 186, © Springer-Verlag Berlin Heidelberg 2008

pharmacological interference, as successfully exemplified by botulinum toxins and viral fusion inhibitors.

The a-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 a-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 a-helices that wind around each other into a superhelix (or a super-coil) 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-trans-duction 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).

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