Editing Wobble base pair

{{Short description|RNA base pair that does not follow Watson-Crick base pair rules}}
{{Technical|date=June 2024}}
[[Image:Wobble.svg|thumb|right|225px|Wobble base pairs for [[inosine]] and [[guanine]]]]

A '''wobble base pair''' is a pairing between two [[nucleotides]] in [[RNA]] molecules that does not follow Watson-Crick [[base pair]] rules.<ref name="Campbell 9th">{{cite book|last1=Campbell|first1=Neil|last2=Reece|first2=Jane B.|title=Biology|date=2011|publisher=Benjamin Cummings|location=Boston|isbn=978-0321558237|pages=[https://archive.org/details/campbellbiologyj00reec/page/339 339–342]|edition=9th|url=https://archive.org/details/campbellbiologyj00reec/page/339}}</ref> The four main wobble base pairs are [[guanine]]-[[uracil]] ('''G-U'''), [[hypoxanthine]]-[[uracil]] ('''I-U'''), [[hypoxanthine]]-[[adenine]] ('''I-A'''), and [[hypoxanthine]]-[[cytosine]] ('''I-C'''). In order to maintain consistency of nucleic acid nomenclature, "I" is used for hypoxanthine because hypoxanthine is the [[nucleobase]] of [[inosine]];<ref name=Kuchin-JMBE>{{cite journal
 |url= http://jmbe.asm.org/asm/index.php/jmbe/rt/printerFriendly/267/html_111|title        = Covering All the Bases in Genetics: Simple Shorthands and Diagrams for Teaching Base Pairing to Biology Undergraduates
 |last         = Kuchin
 |first        = Sergei
 |date         = 19 May 2011
 |journal      = Journal of Microbiology & Biology Education
 |volume       = 12
 |issue        = 1
 |pages        = 64–66
 |doi          = 10.1128/jmbe.v12i1.267
 |pmid         = 23653747
 |pmc          = 3577215
 |quote        = The correct name of the base in inosine (which is a nucleoside) is hypoxanthine, however, for consistency with the nucleic acid nomenclature, the shorthand <nowiki>[</nowiki>I<nowiki>]</nowiki> is more appropriate...
 |archive-url  = https://web.archive.org/web/20131017095541/http://jmbe.asm.org/asm/index.php/jmbe/rt/printerFriendly/267/html_111
 |archive-date = 17 October 2013
 |url-status   = dead
}}</ref>
nomenclature otherwise follows the names of nucleobases and their corresponding nucleosides (e.g., "G" for both guanine and [[guanosine]] – as well as for [[deoxyguanosine]]). The thermodynamic stability of a wobble base pair is comparable to that of a Watson-Crick base pair. Wobble base pairs are fundamental in RNA [[Nucleic acid secondary structure|secondary structure]] and are critical for the proper translation of the [[genetic code]].

==Brief history==
In the [[genetic code]], there are 4<sup>3</sup> = 64 possible codons (three-[[nucleotide]] sequences). For [[translation (genetics)|translation]], each of these codons requires a [[Transfer RNA|tRNA]] molecule with an anticodon with which it can stably complement. If each tRNA molecule is paired with its complementary mRNA codon using canonical Watson-Crick base pairing, then 64 types of tRNA molecule would be required. In the standard genetic code, three of these 64 mRNA codons (UAA, UAG and UGA) are stop codons. These terminate translation by binding to [[release factor]]s rather than tRNA molecules, so canonical pairing would require 61 species of tRNA. Since most organisms have fewer than 45 types of tRNA, ⁣<ref>{{cite web|url=http://gtrnadb.ucsc.edu/|title=Genomic tRNA Database|work=University of California, Santa Cruz|date=18 April 2011|access-date=31 October 2015|first1=Todd|last1=Lowe|first2=Patricia|last2=Chan|archive-url=https://web.archive.org/web/20150530191243/http://gtrnadb.ucsc.edu/|archive-date=30 May 2015|url-status=live}}</ref> some tRNA types can pair with multiple, synonymous codons, all of which encode the same amino acid. In 1966, [[Francis Crick]] proposed the '''''Wobble Hypothesis''''' to account for this. He postulated that the [[Directionality (molecular biology)|5']] base on the anticodon, which binds to the [[Directionality (molecular biology)|3']] base on the [[mRNA]], was not as spatially confined as the other two bases and could, thus, have non-standard base pairing.<ref>{{cite journal|last1=Crick|first1=F.H.C.|title=Codon—anticodon pairing: The wobble hypothesis|journal=Journal of Molecular Biology|date=August 1966|volume=19|issue=2|pages=548–555|doi=10.1016/S0022-2836(66)80022-0|url=http://profiles.nlm.nih.gov/SC/B/C/B/S/_/scbcbs.pdf|pmid=5969078|access-date=31 October 2015|citeseerx=10.1.1.693.2333|archive-url=https://web.archive.org/web/20160304083904/http://profiles.nlm.nih.gov/SC/B/C/B/S/_/scbcbs.pdf|archive-date=4 March 2016|url-status=live}}</ref> Crick creatively named it for the small amount of "play" or wobble that occurs at this third codon position. Movement ("wobble") of the base in the 5' anticodon position is necessary for small conformational adjustments that affect the overall pairing geometry of anticodons of tRNA.<ref>{{cite book|editor1-first=Christopher K.|editor1-last=Mathews|editor2-last=Van Holde|editor2-first=K.E.|editor3-last=Appling|editor3-first=Dean|display-editors = 3 |editor4-last=Anthony-Cahill|editor4-first=Spencer|title=Biochemistry|date=2012|publisher=Prentice Hall|location=Toronto|isbn=978-0-13-800464-4|edition=4th|page=1181}}</ref><ref>{{cite book|last1=Voet|first1=Donald|last2=Voet|first2=Judith|title=Biochemistry|date=2011|publisher=John Wiley & Sons|location=Hoboken, NJ|isbn=9780470570951|pages=1360–1361|edition=4th}}</ref>

As an example, [[yeast]] tRNA<sup>[[Phenylalanine|Phe]]</sup> has the anticodon 5'-GmAA-3' and can recognize the codons 5'-UUC-3' and 5'-UUU-3'. It is, therefore, possible for non-Watson–Crick base pairing to occur at the third codon position, i.e., the 3' [[nucleotide]] of the mRNA codon and the 5' nucleotide of the tRNA anticodon.<ref>{{cite journal|last1=Varani|first1=Gabriele|last2=McClain|first2=William H|title=The G·U wobble base pair|journal=EMBO Reports|date=July 2000|volume=1|issue=1|pages=18–23|doi=10.1093/embo-reports/kvd001|pmid=11256617|pmc=1083677}}</ref>

===Wobble hypothesis===
These notions led [[Francis Crick]] to the creation of the wobble hypothesis, a set of four relationships explaining these naturally occurring attributes.
# The first two bases in the codon create the coding specificity, for they form strong Watson-Crick base pairs and bond strongly to the anticodon of the tRNA.
# When reading [[Directionality (molecular biology)|5']] to [[Directionality (molecular biology)|3']] the first nucleotide in the anticodon (which is on the tRNA and pairs with the last nucleotide of the codon on the mRNA) determines how many nucleotides the tRNA actually distinguishes. <br />If the first nucleotide in the anticodon is a C or an A, pairing is specific and acknowledges original Watson-Crick pairing, that is: only one specific codon can be paired to that tRNA. If the first nucleotide is U or G, the pairing is less specific and in fact two bases can be interchangeably recognized by the tRNA. [[Inosine]] displays the true qualities of wobble, in that if that is the first nucleotide in the anticodon, any of three bases in the original codon can be matched with the tRNA.
# Due to the specificity inherent in the first two nucleotides of the codon, if one [[amino acid]] is coded for by multiple anticodons and those anticodons differ in either the second or third position (first or second position in the codon) then a different tRNA is required for that anticodon.
# The minimum requirement to satisfy all possible codons (61 excluding three stop codons) is 32 tRNAs. That is 31 tRNAs for the amino acids and one initiation codon.<ref>{{cite book|last1=Cox|first1=Michael M.|last2=Nelson|first2=David L.|title=Lehninger Principles of Biochemistry|date=2013|publisher=W.H. Freeman|location=New York|edition=6th|pages=[https://archive.org/details/lehningerprincip00lehn_1/page/1108 1108–1110]|chapter=Protein Metabolism: Wobble Allows Some tRNA's to Recognize More than One Codon|chapter-url=https://books.google.com/books?id=5Ek9J4p3NfkC&pg=PA1067|access-date=31 October 2015|isbn=9780716771081|url=https://archive.org/details/lehningerprincip00lehn_1/page/1108}} <!-- URL for 5th ed. --></ref>

===tRNA base pairing schemes===
Wobble pairing rules. Watson-Crick base pairs are shown in '''bold'''. Parentheses denote bindings that work but will be favoured less. A leading x denotes derivatives (in general) of the base that follows.
{| class="wikitable"
|-
! tRNA 5' anticodon base !! mRNA 3' codon base (Crick)<ref group=note>These relationships can be further observed, as well as full codons and anticodons in the correct reading frame at: {{cite web|last1=SBDR|title=Genetic Code and Amino Acid Translation|url=http://www.soc-bdr.org/rds/authors/unit_tables_conversions_and_genetic_dictionaries/genetic_code_tables/index_en.html|website=Society for Biomedical Diabetes Research|date=2008-04-15|access-date=2014-09-14|archive-url=https://web.archive.org/web/20141104171908/http://www.soc-bdr.org/rds/authors/unit_tables_conversions_and_genetic_dictionaries/genetic_code_tables/index_en.html|archive-date=2014-11-04|url-status=live}} For a modern view on the pairings, see doi:10.1093/nar/gkh185.</ref> !! mRNA 3' codon base (Revised)<ref>{{cite journal|last1=Murphy IV|first1=Frank V|last2=Ramakrishnan|first2=V|title=Structure of a purine-purine wobble base pair in the decoding center of the ribosome|journal=Nature Structural & Molecular Biology|date=21 November 2004|volume=11|issue=12|pages=1251–1252|doi=10.1038/nsmb866|pmid=15558050|s2cid=27022506}}</ref>
|-
|A || '''U''' || '''U''', C, G, or (A)
|-
|C || '''G''' || '''G'''
|-
|G || '''C''' or U || '''C''' or U
|-
|U || '''A''' or G ||  '''A''', G, U, or (C)
|-
|[[Hypoxanthine|I]] || A, C, or U || A, C, or U
|-
| [[Lysidine (nucleoside)|k<sup>2</sup>C]] || || A
|-
|x[[5-methyl-2-thiouridine|m<sup>5</sup>s<sup>2</sup>U]], x[[5-methyl-2'-O-methyluridine|m<sup>5</sup>Um]], [[2'-O-methyluridine|Um]], x[[5-methyluridine|m<sup>5</sup>U]] || || '''A''' or (G)
|-
|x[[5-hydroxyuridine|o<sup>5</sup>U]] || || U, A, or G
|}

==Biological importance==
Aside from the necessity of wobble, that our cells have a limited amount of tRNAs and wobble allows for more flexibility, wobble base pairs have been shown to facilitate many biological functions, most clearly demonstrated in the bacterium ''[[Escherichia coli]]'', a [[model organism]]. In fact, in a study of ''E. coli''{{'}}s [[tRNA]] for [[alanine]] there is a wobble base pair that determines whether the tRNA will be [[Aminoacylation|aminoacylated]]. When a tRNA reaches an [[aminoacyl tRNA synthetase]], the job of the synthetase is to join the t-shaped RNA with its amino acid. These aminoacylated tRNAs go on to the translation of an mRNA transcript, and are the fundamental elements that connect to the codon of the amino acid.<ref name="Campbell 9th"/> The necessity of the wobble base pair is illustrated through experimentation where the Guanine-Uracil pairing is changed to its natural Guanine-Cytosine pairing. Oligoribonucleotides were synthesized on a Gene Assembler Plus, and then spread across a DNA sequence known to code a tRNA for alanine, 2D-NMRs are then run on the products of these new tRNAs and compared to the wobble tRNAs. The results indicate that with that wobble base pair changed, structure is also changed and an [[alpha helix]] can no longer be formed. The alpha helix was the recognizable structure for the aminoacyl tRNA synthetase and thus the synthetase does not connect the amino acid alanine with the tRNA for alanine. This wobble base pairing is essential for the use of the amino acid alanine in ''E. coli'' and its significance here would imply significance in many related species.<ref>{{Cite journal |pmid = 8641457|year = 1996|last1 = Limmer|first1 = S.|title = NMR evidence for helix geometry modifications by a G-U wobble base pair in the acceptor arm of E. Coli tRNA(Ala)|journal = FEBS Letters|volume = 385|issue = 1–2|pages = 15–20|last2 = Reif|first2 = B.|last3 = Ott|first3 = G.|last4 = Arnold|first4 = L.|last5 = Sprinzl|first5 = M.|doi = 10.1016/0014-5793(96)00339-0|doi-access = free| bibcode=1996FEBSL.385...15L }}</ref> More information can be seen on aminoacyl tRNA synthetase and the genomes of ''E. coli'' tRNA at the [[#External links|External links]], ''Information on Aminoacyl tRNA Synthetases'' and ''Genomic tRNA Database''.

==See also==
* [[Base pair]]
* [[Hoogsteen base pair]]
* [[Synonymous substitution]]

==Footnotes==
{{Reflist|group=note}}

==References==
{{Reflist|30em}}

==External links==
*[https://www.mun.ca/biochem/courses/3107/Lectures/Topics/tRNA.html tRNA, the Adaptor Hypothesis and the Wobble Hypothesis]
*[https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.1058 Wobble base-pairing between codons and anticodons]
*[http://www.soc-bdr.org/rds/authors/unit_tables_conversions_and_genetic_dictionaries/genetic_code_tables/index_en.html Genetic Code and Amino Acid Translation]
*[http://dx.doi.org/10.2210/rcsb_pdb/mom_2001_4 Information of Aminoacyl tRNA Synthetases]
*[http://lowelab.ucsc.edu/GtRNAdb/Esch_coli_K12/Esch_coli_K12-structs.html Genomic tRNA Database]

{{DEFAULTSORT:Wobble Base Pair}}
[[Category:Nucleic acids]]
[[Category:Protein biosynthesis]]