Protein Motif (Supersecondary structure)

Protein Motif (Supersecondary structure)

Definition: Simple combinations of few secondary structure elements with a specific geometric arrangement

Why motifs are called super secondary structures?

Answer: Motifs contain more than one secondary structural element. Typically they composed of two secondary structures and a turn or loop.

Occur frequently in protein structures.

All motifs may not necessarily have a biological function. But they are part of larger structural and functional assemblies.

If a motif has biological function (DNA or protein binding, catalytic action), it is called as a Domain

Eg: Zinc-finger motifs (DNA binding). So they are also called Zinc-finger domains.

Leucine zipper motif (found as part of a dimerization domain in many transcription factors).

Motifs are structural feature and Domains are functional regions of a polypeptide

Motifs: structural motif or sequence motif.

Sequence motifs: share certain sequence of amino acids.

Structural motifs: Composed of several secondary structures that are sequential to each other within the protein’s primary structure (e.g. Helix-loop-helix) and are not separated by a random structure.

Simple motifs can combine to form more complex motifs.

Important point: If a motif is cleaved off from a polypeptide chain, it loses its function.

Reason: The structures of motifs are held in place by weak interactions such as hydrogen bond with the rest of the polypeptide chain. When a motif is cleaved off, the weak interaction that holds its specific structure are interrupted. This causes the motif to lose its specific structure. Since the structure determines the function, the cleaved off motif have now lost its function.

Types of Motifs

Different classes (Based on predominant secondary structures present)

All Helix:  Helix-turn-helix, helix-loop-helix, Helix-hairpin-helix, α-α corner, coiled coil, helix bundle

All beta Sheet:  β-hairpins , , β-β corner,  Greek key motif, beta meander, beta sandwich, beta barrel

Mix of helix and sheets:  Rossmann fold, β-α-β loop

Helix – turn – Helix Motif (α – α type)

  • Composed of two anti parallel α helices connected by a turn.
  • Usually identified in proteins that bind to DNA minor and major grooves, and in calcium-binding proteins (Functional motif)
  • Eg:  CAP and λ repressor (Cro).
  • It consists of two segments of alpha helix separated by a short irregular region, or “turn”.
  • Two helices have different function: “Recognition helix”:  Helix that contributes to the DNA recognition
  • Second helix stabilizes the interaction between protein and DNA.
  • HTH is the main DNA-binding motif of prokaryotes.
  • Loops that contain only 4 or 5 amino acid residues are known as turns when they have internal hydrogen bonds.
  • Proteins having this motifs are generally involved in cell proliferation, establishment of DNA structure, developmental regulation, maintenance of circadian rhythms, movement of DNA, regulation of a myriad of bacterial operons and initiation of transcription itself.

Helix – loop – Helix Motif (HLH)

  • Characterizes a family of transcription factors.
  • HLH is one of the DNA-binding motifs found in eukaryotes.
  • The HLH motif is composed of two α helices connected by a loop.
  • A loop implies at least a few residues with no specific secondary structure between two secondary structure elements. They usually contain hydrophilic residues and are found on the protein surface.
  • One helix is smaller and flexible. It allows dimerization by folding and packing against another helix.
  • The larger helix typically contains the DNA- binding regions.
  • HLH proteins typically bind to an E box (CACGTG) consensus sequence.
  • In general, transcription factors containing HLH motifs are dimeric, each with one helix containing basic amino acid residues that facilitate DNA binding.
  • Eg; C-Myc, N-Myc, MyoD etc

Helix – hairpin – helix Motifs

  • DNA- binding proteins with a HhH structural motifs are involved in non-sequence specific DNA binding that occurs via the formation of hydrogen bonds between protein backbone nitrogens and DNA phosphate groups.
  • A hairpin is a particular case of a turn, in which the direction of the protein backbone reverses and the neighboring secondary structure elements interact
  • Eg:  5’-exonuclease domains of prokaryotic DNA polymerases

β- Hairpins

Most simplest super secondary structure. It contains a turn and two strands.

2 anti-parallel beta-strands + beta-turn = beta- hairpin

Widespread in globular proteins.

Also called β-β unit or β –ribbon.

β – β Corner ( β Corner)

  • Consists of two anti-parallel beta strands.
  • Can change the direction abruptly.
  • The angle of change of direction is about 90°.
  • The abrupt angle change is achieved by one strand having a glycine residue and the other hand having a beta bulge
  • No known function.

Greek key motif (ββββ)

  • Formed by four sequentially connected β-strands adjacent to each other (geometrically aligned to each other)
  • Alternate strands runs in the opposite direction.
  • The first strand (N-terminal strand) and the last strand (C- terminal strand) are adjacent to each other and hydrogen bonds exist between them.
  • Connecting loops can be long and include other secondary structures.
  • This type of structure easily form during protein folding
  • Examples of proteins having greek key motif: PapD (a chaperon), nitrite reductase, bacterial cellulase, spherical virus capsid proteins.

Zinc finger motifs

  • Zinc finger proteins in eukaryotic genomes are among the most abundant proteins .
  • These motifs are often repeated in clusters.
  • This structural element is present in DNA binding proteins.
  • It consists of 30 amino acids forming two antiparallel β-sheet strands and one α-helix.
  • The alpha helix of the domain is oriented in such a way that it fits neatly into the major groove of DNA.
  • Side chains are oriented towards the unique functional groups on the edge of DNA bases.
  • Each zinc finger domain has an alpha helix whose side chains interact with individual bases in the major groove of double stranded DNA through hydrogen bonding interactions (bind to DNA in a sequence specific manner)
  • The presence of Zn2+ is crucial for stabilization of the domain. This motif can coordinate one or more zinc atoms.
  • The zinc ion is kept in place by two cysteine (Cys) and two histidine (His) R groups.
  • (2 Cys held in beta sheet and 2 His in alpha helix tetrahedrally coordinated to Zn ion).
  • Proteins with zinc finger domains perform diverse functions in the cell:  DNA recognition, RNA packaging, transcriptional activation, regulation of apoptosis, protein folding and assembly, and lipid binding.


The transcription factor TFIIIA has up to 9 zinc fingers that interact with the promoter sequence of DNA where it recruits RNA polymerase and induces transcription of the 5S rRNA gene.

The PARP protein has two zinc finger domains that bind specifically to DNA sites with single strand breaks and repairs the damage.

Coiled coil motif

  • Here 2 to 7 alpha helices are coiled together like a strand of rope.
  • Proteins with this motif are mainly involved in biological functions like regulation of gene expression.
  • Eg: Tropomyosin (muscle protein), transcription factors, onco proteins c-Fos, c –jun etc

α α corner motif

  • Short  loop region connecting the two helices in the motif.
  • Two helices in this motif are roughly perpendicular to one another.
  • These kinds of motifs are common on some DNA binding proteins

Rossman fold

  • Proteins that bind nucleotides contain this type of motif (eg: enzyme cofactors FAD, NAD+, and NADP+).
  • This fold is composed of alternating beta strands and alpha helical segments.
  • The beta strands are hydrogen bonded to each other forming a beta sheet. Alpha helices surround the sheet on both sides . This kind of arrangement produce a 3 layered sandwich structure.
  • The structure consists of up to seven beta strands, mostly parallel.

Helix bundles

  • It is long stretches of a polar aminoacids fold into trans membrane α-helices.
  • A helix bundle is a small protein fold consisting of several alpha helices, usually almost parallel or antiparallel to one another.
  • Proteins with a four-helix bundle structure include growth hormones, cytokines, and ferritins.
  • Helices can be either parallel or anti parallel in a four helix bundle .
  • In cytochrome b562 adjacent helices are antiparallel.
  • In human growth hormone two pairs of parallel a helices (2 parallel and 2 anti parallel helices).

β- Barrels

  • Number of β-sheets are twisted and coiled into a cylinder form.
  • The first strand in the barrel is hydrogen bonded to the last strand.
  • Beta strands in beta-barrels are typically arranged in an antiparallel fashion.
  • Here the hydrophobic side chains line in the outer surface to interact with the lipid bilayer.
  • Eg: beta-Barrel proteins are found in the outer membranes of bacteria, mitochondria and chloroplasts.

β-α-β loop

  • There is a long crossover between the end of the first beta strand and the beginning of the second beta strand frequently made by a helix.
  • The hydrophobic core is buried between the α helix and β sheets.
  • The first loop is often preserved evolutionarily, while the second loop seldom has a known function.
  • Helix above the plane is Right-handed
  • Helix below the plane is Left-handed.

β-β corner

A beta-beta-corner can be represented as a long beta-beta-hairpin folded orthogonally on itself so that the strands, when passing from one layer to the other, rotate in a right-handed direction about an imaginary axis.

β meander

  • Supersecondary structure composed of 2 or more consecutive anti parallel beta strands, which are linked together by hairpin loops.
  • This motif is common in beta sheets
  • Also found in beta barrels and beta propellers (structural architectures)

β sandwich

  • The β-sandwich topology first identified in the domains of immunoglobulin (Ig) structures.
  • The primary sequence of the motif contains 80 to 350 aminoacids.
  • The motif contain two anti-parallel β-sheets packed face to face (the number of β-strands is variable between different proteins).
  • β – Sandwich domains are subdivided in a variety of different folds.
  • The immunoglobulin type fold: Found in antibodies (Ig – fold). It consists of a sandwich arrangement of 7 and 9 antiparallel arranged in two β sheets with a Greek key topology.
  • The jelly – roll topology is found in concanavalin A(carbohydrate binding proteins)
  • Location: This motif characteristically occurs within the extracellular portions of proteins.

Function:  Frequently mediates recognition events.


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