Leucine Zippers


The leucine zipper (ZIP) motif consists of a periodic repetition of a leucine residue at every seventh position (heptad repeat) and forms an α‐helical conformation, which facilitates dimerisation and in some cases higher oligomerisation of proteins by forming a parallel helix–helix association stabilised by formation of an interhelical hydrophobic core involving leucine side chains. These nonpolar interactions are important for stabilisation of the ZIP structures, whereas specificity of these dimerisation and oligomerisation is mediated by electrostatic interactions, such as formation of salt bridges. In many eukaryotic gene regulatory proteins, the ZIP motif is flanked at its N‐terminus by a basic region containing characteristic residues that facilitate deoxyribonucleic acid (DNA) binding and is referred to as bZIP. ZIP‐related heptad repeats are frequently found in a variety of proteins and catalyse dimerisation/oligomerisation by forming both parallel and antiparallel coiled coils.

Key Concepts:

  • A heptad repeat of leucine residues, leucine zipper (ZIP), is an important sequence motif facilitating protein–protein interactions.

  • ZIP forms an amphiphilic α helical structure, in which two residues that are separated by seven residues in sequence are located at nearly the same molecular surface in an α helix.

  • The amphiphilic nature of the ZIP helix facilitates protein dimerisation by forming a parallel helix–helix association.

  • Leucine side chains extending from one α helix interdigitate with those displayed from an α helix of a second polypeptide like a zipper to stabilise formation of an interhelical hydrophobic core.

  • The specificity of the ZIP dimerisation is mediated by electrostatic interactions, such as formation of salt bridges.

  • ZIP is frequently fused with other sequence motifs to produce biologically important functional structural modules.

  • The ‘basic region ZIP’ (bZIP motif) is a fusion between a segment that is rich in basic residues facilitating DNA binding and ZIP, forming a class of eukaryotic transcription factors.

  • The DNA binding specificity of bZIP is determined by the basic region that directly binds a class of palindromic DNA sequences.

  • ZIP‐related sequence motifs containing an incomplete heptad repeat are frequently found in a variety of proteins and catalyse dimerisation/oligomerisation by forming both parallel and antiparallel coiled coils.

Keywords: ZIP; dimerisation; coiled coil; bZIP; transcription factors; nonpolar contact; salt bridge

Figure 1.

Parallel coiled‐coil structure of GCN4 ZIP homodimer (Protein Data Bank (PDB) accession code 1gd2). The main chains of the two peptide chains are represented as ribbons in grey. The side chains participating in the dimer association are represented as stick models with carbon atoms in brown, nitrogen atoms in blue and oxygen atoms in red. The positions of the heptad repeat are labelled ag. The d‐positioned leucines are boxed and highlighted in green with underline. The a‐positioned residues are highlighted in blue. Unusually, this GCN4 ZIP motif has a polar asparagine residue in the a position located at the middle of the ZIP motif.

Figure 2.

Pap1 bZIP homodimer bound to DNA (PDB accession code 1gd2). The basic region of the ZIP motif is shown in blue and the ZIP motif in green. The double‐stranded DNA fragment is shown as a purple stick model. The basic regions that flank the ZIP coiled coil bind DNA with sequence‐specific interactions.

Figure 3.

Interchain polar interactions found in the coiled‐coil structure of the Fos–Jun ZIP heterodimer (PDB accession code 1fos). Hydrogen bonding interactions are indicated by dotted lines. The dimerisation specificity is primarily determined by polar interactions involving the side chains of residues at the e and g positions. A few polar residues at the a positions also contribute to the specificity.

Figure 4.

Internal interactions of polar residues in a and d positions in the coiled‐coil structure of the Pap1 ZIP dimer. Part of the coiled‐coil structure is presented to show that His115 in the a position and Thr118 in the d position form water‐mediated hydrogen bonds at the coiled‐coil interface. Polar residues Asn122 in the a position and Asp123 in the g position also form interchain hydrogen bonds.



Crick FHC (1953) The packing of α‐helices: simple coiled‐coils. Acta Crystallographica 6: 689–697.

Ellenberger TE, Brandl CJ, Struhl K and Harrison SC (1992) The GCN4 basic region leucine zipper binds DNA as a dimer of uninterrupted α helices: Crystal structure of the protein–DNA complex. Cell 71: 1223–1237.

Fujii Y, Shimizu T, Toda T, Yanagida Y and Hakoshima T (2000) Structural basis for the diversity of DNA recognition by bZIP transcription factors. Nature Structural Biology 7: 889–893.

Glover JNM and Harrison SC (1995) Crystal structure of heterodimeric bZIP transcription factor c‐Fos–c‐Jun bound to DNA. Nature 373: 257–261.

Hirano Y, Hatano D, Takohashi A et al. (2011) Structural basis of cargo recognition by the myosin‐X MyTH4‐FERM domain. EMBO Journal 30: 2734–2747.

Landschulz WH, Johnson PF and McKnight SL (1988) The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science 240: 1759–1764.

Maesaki R, Ihara K, Shimizu T et al. (1999) The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1. Molecular Cell 4: 793–803.

Schultz J, Copley RR, Doerks T, Ponting CP and Bork P (2000) SMART: a web‐based tool for the study of genetically mobile domains. Nucleic Acids Research 28: 231–234.

Further Reading

Baranger AM (1998) Accessory factor–bZIP–DNA interactions. Current Opinion in Chemical Biology 2: 18–23.

Branden C and Tooze J (1998) Alpha‐domain structures. Introduction to Protein Structure, 2nd edn, pp. 35–46. New York, NY: Garland.

Burkhard P, Strelkov SV and Stetefeld J (2001) Coiled coils: a highly versatile protein folding motif. Trends in Cell Biology 11: 82–88.

Hurst HC (1994) Transcription factors. 1: BZIP proteins. Protein Profile 1: 123–168.

O'Shea EK, Rutkowski R and Kim PS (1989) Evidence that the leucine zipper is a coiled coil. Science 243: 538–542.

O'Shea EK, Rutkowski R and Kim PS (1992) Mechanism of specificity in the Fos–Jun oncoprotein heterodimer. Cell 68: 699–708.

Vinson CR, Hai T and Boyd SM (1993) Dimerization specificity of the leucine zipper‐containing bZIP motif on DNA binding: prediction and rational design. Genes and Development 7: 1047–1058.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Hakoshima, Toshio(Apr 2014) Leucine Zippers. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005049.pub2]