I have two different proteins that are predicted to have an affinity with a cellular receptor (i.e., TLR4), however, their binding sites are different (one protein binds at the head of the receptor while the other binds at its groove). Would both initiate downstream signaling pathways?
Hello Sitara Nasar
Toll-like receptors (TLRs) are essential components of the innate immune system. Structurally, TLR4 forms a complex on the cell surface with several other proteins needed for ligand recognition. These are proteins which based on their functions are classified as ligand recognition and delivery cofactors, chaperones and trafficking proteins. Because of their essential roles in TLR function, you need to look at these accessory proteins as well which may benefit strategies aimed at manipulating TLR activation.
For instance, TLR4 is activated by lipopolysaccharide (LPS, endotoxin), a major component of the outer membrane of Gram-negative bacteria. During infection, TLR4 responds to the LPS present in tissues and the bloodstream and triggers pro-inflammatory reactions facilitating eradication of the invading bacteria.
The interaction of LPS with TLR4 is not that simple. You need to understand the events following LPS binding to TLR4. Intracellular events following the formation of this receptor complex depend on different sets of adapters.
LPS binds with the help of CD14, to MD-2 and TLR4. CD14 is a glycosylphosphatidylinositol (GPI)-anchored protein localized in the plasma membrane and considered as sites of TLR4 activation. CD14 can transfer the LPS molecule to the TLR4/MD-2 complex. LPS is bound in the N-terminal hydrophobic pocket of CD14. The CD14 hydrophobic pocket probably accommodates up to five acyl chains of the endotoxin while the remaining one can facilitate the association of the CD14-LPS complex with MD-2. This interaction of TLR4/MD-2 with LPS induces homodimerization of TLR4, which in turn recruits MyD88 and Mal to the receptor complex which later triggers a signaling cascade.
Best.
Thank you very much Malcolm Nobre for your answer.
The protein I am referring to is a Virus protein reported to cause pathological response upon its binding to the TLR4 receptor. I have modified this protein and predicted its affinity with the TLR4 receptor through docking. The comparative analysis of both predicted models (unmodified protein Vs modified protein) tells that both proteins have affinity with TLR4 receptor but their binding sites are different. I want to know whether is it possible that a different binding pattern, in the case of unmodified protein with TLR4, would somehow attenuate the pathological response, mentioned earlier.
You have given an example related to LPS which binds to TLR4 in association with CD14. So, do all ligands have to form a complex with CD14 before binding with TLR4? If not, In reference to your example, my question would be, is it possible that by modifying Lipid moiety or by using different sugar molecules LPS still binds to TLR4, but fails to initiate the downstream signaling pathway?
Hope you get my question.
For EGFR, I think the different binding sites cause different effects. There, the functional form of the receptor is the dimer, and it may make a difference.
Thank you very much Carol A Heckman for your answer. Can you kindly share the reference that supports your answer?
We wrote a review a few years ago. It's probably in there.
http://www.researchtrends.net/tia/title_issue.asp?id=57&type=3&in=0&vn=13
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