Knobs-into-holes

The ways in which a-helices pack against one another were initially described by Crick (1953) as knobs into holes side chain packing which could work at either a shallow left-handed crossing angle or a... 

Knobs-into-holes bonding 71,334 in coiled coil 71... 

Coiled-coil helices usually have one stripe of residues engaged in knobs-into-holes interactions. There are, however, instances where a helix may engage in such interactions along two stripes (Cohen and Parry, 1990 Walshaw and Woolfson, 2003 Walshaw et ah, 2001). For example, helices of four-stranded coiled coils make their primary knobs-into-holes contacts... 

Fig. 9. Coiled-coil spirals. For the phage coat proteins and flagellin, subunits are shown enlarged next to the structures, as well as the cross sections of the coiled-coil sheets they form. The positions of the subunits in the structures are indicated in white. The core packing layers are also shown for the phage coat proteins in order to illustrate the use of knobs-into-holes and ridges-into-grooves layers.

Fig. 12. Coiled coils arising between helices that are part of different folds, (a) Soluble proteins, (b) Example of a membrane protein. Inner membrane proteins are Q-helical proteins with an up-and-down topology their helices therefore favor low crossing angles and frequently show mixtures of knobs-into-holes and ridges-into-...

Walshaw, J., and Woolfson, D. N. (2003). Extended knobs-into-holes packing in classical and complex coiled-coil assemblies./. Struct. Biol. 144, 349-361. 

A coiled coil is a protein bundle of 2-5 alpha helices wrapped around each other into a superhelix, also called a supercoil (Lupas, 1996a Mason and Arndt, 2004 Lupas and Gruber, 2005). In the simplest form of coiled coil, helical domains of two proteins wind around one another and bind via a distinctive knobs-into-holes pattern whereby an amino acid side chain of one helix (knob) inserts into a space surrounded by four side chains of the facing helix (hole) as first suggested by Francis Crick in 1952 (Lupas, 1996a Lupas and Gruber, 2005). 

The Leucine Zipper (LZ) is a dimerization motif found in the b-LZ and b-HLH-LZ ttanscription factor families (1,2). Upon dimerization, LZs fold into parallel and two-stranded a-helical coiled-coils (3-6). The primary structure of coiled-coils forming proteins is characterized by the heptad repeats (abcdefg)n where Leu residues are conserved at positions d and positions a are mostly occupied by P-branched and hydrophobic residues while e and g positions are often occupied by acidic or basic residues (7,8). The tertiary interactions of the dimeric LZ or parallel and two-stranded a-helical coiled-coils are described by the knobs-into-holes model (3,9). 

Figure 1. A. Primary structures of the c-Myc and Max LZs. Sequences are taken from Zervo a al. (26) and renumbered. B. Helical wheel diagram of the c-Myc-Max heterodimeric LZ. Potential interhelical electrostatic interactions have been discussed elsewhere (19,20). In the knobs-into-hole model (9), side-chains (knobs) at position <1 in the heptad repeat pack in the holes formed by consecutive g and a residues and two d positions. Accordingly, Max AsnSn is proposed to pack in the hole formed by Valid, Glu4g, GluSa and LeuSd on the c-Myc LZ. Similarly, Max Asnl9a is proposed to pack in the hole formed by LeulSd, ArglSg, Argl9a and Leu22d.

The NOEs from H5 protons of Max Asn 5a and Max Asn 19a connect these side-chains to the residues on the c-Myc LZ that form the holes in which they would pack according to the knobs-into-holes model (see legend of Fig.l). This strongly supports the proposition that both Asn side-chains are buried at the interface of the c-Myc-Max heterodimeric LZ. 

Amphipathic a-heUces associate via their hydrophobic faces in a knobs-into-holes side-chain arrangement, a-Hehces are characterized by heptad repeats (repeated seven residues, a-g, within heUx). The helices interact via hydrophobic residues between residues a and d to form an apolar stripe along one side and an electrostatic interaction between residues e and g on the other side of each helix. 

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