Sequential model: Difference between revisions

Revision as of 02:22, 5 March 2017

Revision as of 06:47, 25 March 2017

Line 1:

{{Refimprove|date=March 2017}}

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

Biochemistry 5, 365–385. [http://pubs.acs.org/doi/abs/10.1021/bi00865a047 DOI: 10.1021/bi00865a047]</ref> It postulates that a protein's conformation changes with each binding of a [[Ligand (biochemistry)|ligand]], thus sequentially changing its affinity for the ligand at neighboring binding sites.

[[File:KNF_model.gif|thumb|Visual representation of the KNF model in a tetrameric protein.|433x433px]]

Line 25:

== Comparison to the MWC Model ==

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 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}}</ref>

=== 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}}</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.

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 Hamadi, 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|last=Cui|first=Qiang|last2=Karplus|first2=Martin|date=2017-03-25|title=Allostery and cooperativity revisited|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2492820/|journal=Protein Science : A Publication of the Protein Society|volume=17|issue=8|pages=1295–1307|doi=10.1110/ps.03259908|issn=0961-8368|pmc=PMC2492820|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|pages=1707-1710|via=}}</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==