Triple helix

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a molecular model of the collagen triple helix
The collagen triple helix is a triple helix formed from three separate protein helices, spiraling around the same axis.

In the fields of geometry and biochemistry, a triple helix (plural triple helices) is a set of three congruent geometrical helices with the same axis, differing by a translation along the axis. This means that each of the helices keeps the same distance from the central axis. As with a single helix, a triple helix may be characterized by its pitch, diameter, and handedness. Examples of triple helices include triplex DNA,[1] triplex RNA[2] collagen[3] and collagen-like proteins.

Structure[edit]

A triple helix is named such because it is made up of three separate helices. Each of these helices shares the same axis, but they do not take up the same space because each helix is translated angularly around the axis. Generally, the identity of a triple helix depends on the type of helices that make it up. For example: a triple helix made of three strands of collagen protein is a collagen triple helix, and a triple helix made of three strands of DNA is a DNA triple helix.

As with other types of helices, triple helices have handedness: right-handed or left-handed. A right-handed helix moves around its axis in a clockwise direction from beginning to end. A left-handed helix is the right-handed helix's mirror image, and it moves around the axis in a counterclockwise direction from beginning to end.[4] The beginning and end of a helical molecule are defined based on certain markers in the molecule that do not change easily. For example: the beginning of a helical protein is its N terminus, and the beginning of a single strand of DNA is its 5' end.[4]

The collagen triple helix is made of three collagen peptides, each of which forms its own left-handed polyproline helix.[5] When the three chains combine, the triple helix adopts a right-handed orientation. The collagen peptide is composed of repeats of Gly-X-Y, with the second residue (X) usually being Pro and the third (Y) being hydroxyproline.[6][5]

A DNA triple helix is made up of three separate DNA strands, each oriented with the sugar/phosphate backbone on the outside of the helix and the bases on the inside of the helix. The bases are the part of the molecule closest to the triple helix's axis, and the backbone is the part of the molecule farthest away from the axis. The third strand occupies the major groove of relatively normal duplex DNA.[7] The bases in triplex DNA are arranged to match up according to a Hoogsteen base pairing scheme.[8] Similarly, RNA triple helices are formed as a result of a single stranded RNA forming hydrogen bonds with an RNA duplex; the duplex consists of Watson-Crick base pairing while the third strand binds via Hoogsteen base pairing.[9]

Stabilizing factors[edit]

The collagen triple helix has several characteristics that increase its stability. When proline is incorporated into the Y position of the Gly-X-Y sequence, it is post-translationally modified to hydroxyproline.[10] The hydroxyproline can enter into favorable interactions with water, which stabilizes the triple helix because the Y residues are solvent-accessible in the triple helix structure. The individual helices are also held together by an extensive network of amide-amide hydrogen bonds formed between the strands, each of which contributes approximately -2 kcal/mol to the overall free energy of the triple helix.[5] The formation of the superhelix not only protects the critical glycine residues on the interior of the helix, but also protects the overall protein from proteolysis.[6]

Triple helix DNA and RNA are stabilized by many of the same forces that stabilize double-stranded DNA helices. With nucleotide bases oriented to the inside of the helix, closer to its axis, bases engage in hydrogen bonding with other bases. The bonded bases in the center exclude water, so the hydrophobic effect is particularly important in the stabilization of DNA triple helices.[4]

Biological role[edit]

Proteins[edit]

Members of the collagen superfamily are major contributors to the extracellular matrix. The triple helical structure provides strength and stability to collagen fibers by providing great resistance to tensile stress. The rigidity of the collagen fibers is an important factor that can withstand most mechanical stress, making it an ideal protein for macromolecular transport and overall structural support throughout the body.[6]

DNA[edit]

There are some oligonucleotide sequences, called triplet-forming oligonucleotides (TFOs) that can bind to form a triplex with a longer molecule of double-stranded DNA; TFOs can inactivate a gene or help to induce mutations.[7] TFOs can only bind to certain sites in a larger molecule, so researchers must first determine whether a TFO can bind to the gene of interest.

RNA[edit]

In recent years, the biological function of triplex RNA has become more studied. Some roles include increasing stability, translation, influencing ligand binding, and catalysis. One example of ligand binding being influenced by a triple helix is in the SAM-II riboswitch where the triple helix creates a binding site that will uniquely accept S-adenosylmethionine (SAM).[9] The ribonucleoprotein complex telomerase, responsible for replicating the tail-ends of DNA (telomeres) also contains triplex RNA believed to be necessary for proper telomerase functioning.[9][11] The triple helix at the 3' end of MALAT1 serves to stabilize the RNA by protecting the Poly-A tail from proteolysis as well as increases translation efficiency, which is ultimately detrimental to humans as MALAT1 is related to lung cancer malignancy.[9][12]

References[edit]

  1. ^ Bernués J, Azorín F (1995). "Triple-stranded DNA.". Nucleic Acids and Molecular Biology. Berlin, Heidelberg: Springer. pp. 1–21. doi:10.1007/978-3-642-79488-9_1.
  2. ^ Buske FA, Mattick JS, Bailey TL (May 2011). "Potential in vivo roles of nucleic acid triple-helices". RNA Biology. 8 (3): 427–39. doi:10.4161/rna.8.3.14999. PMC 3218511. PMID 21525785.
  3. ^ Bächinger HP (2005-05-03). Collagen: Primer in Structure, Processing and Assembly. Springer Science & Business Media. ISBN 9783540232728.
  4. ^ a b c John,, Kuriyan,. The molecules of life : physical and chemical principles. Konforti, Boyana,, Wemmer, David,. New York. ISBN 9780815341888. OCLC 779577263.
  5. ^ a b c Shoulders MD, Raines RT (2009). "Collagen structure and stability". Annual Review of Biochemistry. 78: 929–58. doi:10.1146/annurev.biochem.77.032207.120833. PMC 2846778. PMID 19344236.
  6. ^ a b c Fidler AL, Boudko SP, Rokas A, Hudson BG (April 2018). "The triple helix of collagens - an ancient protein structure that enabled animal multicellularity and tissue evolution". Journal of Cell Science. 131 (7): jcs203950. doi:10.1242/jcs.203950. PMC 5963836. PMID 29632050.
  7. ^ a b Jain A, Wang G, Vasquez KM (August 2008). "DNA triple helices: biological consequences and therapeutic potential". Biochimie. 90 (8): 1117–30. doi:10.1016/j.biochi.2008.02.011. PMC 2586808. PMID 18331847.
  8. ^ Duca M, Vekhoff P, Oussedik K, Halby L, Arimondo PB (September 2008). "The triple helix: 50 years later, the outcome". Nucleic Acids Research. 36 (16): 5123–38. doi:10.1093/nar/gkn493. PMC 2532714. PMID 18676453.
  9. ^ a b c d Conrad NK (2014). "The emerging role of triple helices in RNA biology". Wiley Interdisciplinary Reviews: RNA. 5 (1): 15–29. doi:10.1002/wrna.1194. PMC 4721660. PMID 24115594.
  10. ^ Brodsky B, Persikov AV (2005-01-01). "Molecular structure of the collagen triple helix". Advances in Protein Chemistry. 70: 301–39. doi:10.1016/S0065-3233(05)70009-7. PMID 15837519.
  11. ^ Theimer CA, Blois CA, Feigon J (March 2005). "Structure of the human telomerase RNA pseudoknot reveals conserved tertiary interactions essential for function". Molecular Cell. 17 (5): 671–82. doi:10.1016/j.molcel.2005.01.017. PMID 15749017.
  12. ^ Brown JA, Bulkley D, Wang J, Valenstein ML, Yario TA, Steitz TA, Steitz JA (July 2014). "Structural insights into the stabilization of MALAT1 noncoding RNA by a bipartite triple helix". Nature Structural & Molecular Biology. 21 (7): 633–40. doi:10.1038/nsmb.2844. PMC 4096706. PMID 24952594.