Sequential model: Difference between revisions

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== Rules Guiding the KNF Model ==

The KNF model follows the structural theory of the induced fit model of substrate binding to an enzyme.<ref name=":1" /> A slight change in the conformation of an enzyme improves its binding affinity to the transition state of the ligand, thus catalyzing a reaction. This follows the KNF model, which models cooperativity as the changing conformation of the ligand binding site upon ligand binding to another subunit.

Two essential assumptions guide the KNF model:<ref name=":2">{{Cite book|url=https://www.worldcat.org/oclc/837581840|title=Structure and mechanism in protein science : a guide to enzyme catalysis and protein folding|last=Alan|first=Fersht,|publisher=Freeman|isbn=9780716732686|oclc=837581840}}</ref>

# The protein exists in a single state of either low or high affinity for the ligand, when not bound to the ligand

# Upon ligation of a binding site, a conformational change is produced in that region of the protein. Changing this region of the protein may influence the conformation of nearby binding sites on the same protein, thus changing their affinity for the ligand. In negative cooperativity, affinity goes from high to low, while in positive cooperativity, affinity goes from low to high.

The KNF model characterizes enzymes that exhibit what was coined by Koshland and Hamadi in 2002 as i³ cooperativity.<ref name=":0" /> This term is used merely to describe the structural nature of the sequential model, as the authors provide no other proposed descriptions or types of cooperativity.<ref>{{Cite book|url=https://books.google.com/books?id=SkSQNNACcrYC&pg=PA687&lpg=PA687&dq=i3+cooperativity&source=bl&ots=MpHL74MyF2&sig=3a-2zLKTyrot0WcQxpe3qZaYGqY&hl=en&sa=X&ved=0ahUKEwjW8aW_7r3SAhUnxlQKHX5oDCsQ6AEIKjAC#v=onepage&q=i3%20cooperativity&f=false|title=Enzyme Kinetics: Catalysis and Control: A Reference of Theory and Best-Practice Methods|last=Purich|first=Daniel L.|date=2010-06-16|publisher=Elsevier|isbn=9780123809254|language=en}}</ref> These three properties are as follows:

The KNF model most often characterizes enzymes that exhibit i³ cooperativity<ref name=":0" /> These three properties are as follows:

# the nature of the subunits of the multimeric protein are such that they are ''identical'' to each other

# ligand binding ''induces'' a conformational change in the protein

# the conformational change is an ''intramolecular'' rearrangement within the protein

The i³ nature of a multimeric, cooperatively-acting protein is useful in standardizing the structural and physical basis of the sequential model.

# the nature of the subunits of the multimeric protein are such that they are ''identical'' to each other

i³ characteristics of a multimeric protein are useful in standardizing the way in which cooperativity is studied, as enzymes are assumed to have these characteristics when operativity cooperatively.

== 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, i.e. 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, resulting in a fixed quaternary state.<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=":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" /> Positive cooperativity is seen to thus have a slight evolutionary advantage over negative cooperativity.

==References==