Sequential model: Difference between revisions

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{{Short description|Type of model used in biochemistry}}

{{More citations needed|date=March 2017}}

The '''sequential model''' (also known as the '''KNF model''') is a theory that describes [[cooperativity]] of [[protein subunit]]s.<ref name=":3"> [[Daniel E. Koshland Jr.|Koshland, D.E.]], Némethy, G. and Filmer, D. (1966) Comparison of experimental binding data and theoretical models in proteins containing subunits.

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Unlike the MWC model, the KNF model offers the possibility of "negative cooperativity".<ref name=":0" /><ref name=":2" /> This term describes a reduction in the affinity of the other binding sites of a protein for a ligand after the binding of one or more of the ligand to its subunits. The MWC model only allows for positive cooperativity, where a single conformational switch from the T to R states results in an increase in affinity for the ligand at unligated binding sites. Ligand binding to the T state thus cannot increase the amount of the protein in the T, or low-affinity, state.

Negative cooperativity is observed in a number of biologically significant molecules, including [[tyrosyl-tRNA synthetase]] and [[glyceraldehyde-3-phosphate dehydrogenase]].<ref name=":5" /><ref name=":2" /> In fact, in a systematic literature review performed in 2002 by Koshland and Hamadani, the same literature review that coined i³ cooperativity, negatively cooperating proteins are seen to compose slightly less than 50% of scientifically studied proteins that exhibit cooperativity, while positively cooperating proteins compose the other, slightly greater than 50%.<ref name=":0" />

=== Functional differences in hemoglobin ===

[[Hemoglobin]], a tetrameric protein that transports four molecules of [[Molecular oxygen|oxygen]], is a highly biologically relevant protein that has been a subject of debate in allostery. It exhibits a sigmoidal binding curve, indicating cooperativity. While most scientific evidence points to concerted cooperativity,<ref name=":6">{{Cite journal|last1=Cui|first1=Qiang|last2=Karplus|first2=Martin|date=2017-03-25|title=Allostery and cooperativity revisited|journal=Protein Science|volume=17|issue=8|pages=1295–1307|doi=10.1110/ps.03259908|issn=0961-8368|pmc=2492820|pmid=18560010}}</ref><ref>{{Cite journal|last1=Berg|first1=Jeremy M.|last2=Tymoczko|first2=John L.|last3=Stryer|first3=Lubert|date=2002-01-01|title=Hemoglobin Transports Oxygen Efficiently by Binding Oxygen Cooperatively|url=https://www.ncbi.nlm.nih.gov/books/NBK22596/|archive-url=https://web.archive.org/web/20210413211652/https://www.ncbi.nlm.nih.gov/books/NBK22596/|url-status=dead|archive-date=April 13, 2021|language=en}}</ref> research into the affinities of specific heme subunits for oxygen has revealed that under certain physiological conditions, the subunits may display properties of sequential allostery.<ref name=":7">{{Cite journal|last=Lindstrom|first=Ted|year=1972|title=Functional nonequivalence of alpha and beta hemes in human adult hemoglobin|journal=Proceedings of the National Academy of Sciences|volume=69|issue=7|pages=1707–1710|doi=10.1073/pnas.69.7.1707|pmid=4505648|pmc=426783|bibcode=1972PNAS...69.1707L|doi-access=free}}</ref> [[Nuclear magnetic resonance]] (NMR) studies show that in the presence of phosphate, deoxygenated human adult hemoglobin's alpha heme subunits display increased affinity for molecular oxygen, when compared to beta subunits. The results suggest either a modified concerted model, in which alpha subunits have a greater affinity for oxygen in the quaternary low-affinity T state, or a sequential model, in which phosphate binding creates a partially oligomerized state that stabilizes a low affinity form of the beta subunits, distinct from a T or R state.<ref name=":7" /> Thus, depending on physiological conditions, a combination of the MWC and KNF models appears to most comprehensively describe hemoglobin's binding characteristics.<ref name=":6" />

==References==