Sequential model: Difference between revisions

Revision as of 08:24, 23 January 2019

Revision as of 07:15, 20 February 2019

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==Overview==

This model for [[allosteric regulation]] of [[enzyme]]s suggests that the [[Protein subunit|subunits]] of multimeric proteins have two conformational states.<ref name=":3" /> The binding of the ligand causes conformational change in the other subunits of the multimeric protein. Although the subunits go through conformational changes independently (as opposed to in the [[MWC model]]), the switch of one subunit makes the other subunits more likely to change, by reducing the energy needed for subsequent subunits to undergo the same conformational change. In elaboration, the binding of a ligand to one subunit changes the protein's shape, thereby making it more [[Thermodynamic free energy|thermodynamically favorable]] for the other subunits to switch conformation to the high affinity state. Ligand binding may also result in negative cooperativity, or a reduced affinity for the ligand at the next binding site, a feature that makes the KNF model distinct from the MWC model, which suggests only positive cooperativity.<ref name=":0">{{Cite journal|last=Koshland|first=Daniel E.|last2=Hamadani|first2=Kambiz|date=2002-12-06|title=Proteomics and Models for Enzyme Cooperativity|url=http://www.jbc.org/content/277/49/46841|journal=Journal of Biological Chemistry|language=en|volume=277|issue=49|pages=46841–46844|doi=10.1074/jbc.R200014200|issn=0021-9258|pmid=12189158}}</ref><ref name=":5">{{Cite journal|last=Henis|first=Y I|last2=Levitzki|first2=A|date=1980-09-01|title=Mechanism of negative cooperativity in glyceraldehyde-3-phosphate dehydrogenase deduced from ligand competition experiments.|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=77|issue=9|pages=5055–5059|issn=0027-8424|pmc=349994|pmid=6933545|doi=10.1073/pnas.77.9.5055}}</ref> It is named KNF after [[Daniel_E._Koshland_Jr.|Koshland]], Némethy and Filmer, who first suggested the model .<ref name=":3" />

== History ==

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=== Structural Differences ===

The primary differentiating feature between the MWC model and KNF model lies in the scale of conformational changes.<ref name=":2" /> While both suggest that a protein's affinity for a given ligand changes upon binding of the ligand, the MWC model suggests that this occurs by a quaternary conformational change that involves the entire protein, moving from T state to favoring the R state. On the other hand, the KNF model suggests these conformational changes occur on the level of tertiary structure within the protein, as neighboring subunits change conformation with successive ligand binding.<ref>{{Cite journal|last=Ronda|first=Luca|last2=Bruno|first2=Stefano|last3=Bettati|first3=Stefano|date=2013-09-01|title=Tertiary and quaternary effects in the allosteric regulation of animal hemoglobins|url=http://www.sciencedirect.com/science/article/pii/S157096391300126X|journal=Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics|series=Oxygen Binding and Sensing Proteins|volume=1834|issue=9|pages=1860–1872|doi=10.1016/j.bbapap.2013.03.013|pmid=23523886}}</ref>

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.

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=== 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|last=Cui|first=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|last=Berg|first=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/|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|url=http://www.pnas.org/content/69/7/1707.full.pdf|journal=Proceedings of the National Academy of Sciences|volume=69|issue=7|pages=1707–1710|via=|doi=10.1073/pnas.69.7.1707|pmid=4505648|pmc=426783}}</ref>[[Nuclear magnetic resonance]] (NMR) studies show that in the presence of phosphate, deoxygenated human adult hemolglobin'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==