2
$\begingroup$

Recently, I've been reading about the MyD88 dependent signalling pathway, with particular reference to its activation in Macrophages and other cells of the immune system on recognition of a pathogen. I understand that when a PAMP (Pathogen Associated Molecular Pattern) binds with a PRR (Pattern Recognition Receptor), the receptor undergoes a conformational change, which precipitates a cascade of chemical reactions between various proteins, which eventually leads (inter alia) to the translocation of NF-κB to the nucleus, which leads to the production of cytokines. My question is about the finer points, particularly with respect to TLR1 and TLR2.

My reading suggests that these generally form a heterodimer - is this always true? Are both required for a pathogen to be recognised and an immune response produced?

Upon the pathogen binding with TLR1 (whether in a complex with TLR2 or not) what precisely happens to the receptor. I understand that MyD88 is, ultimately, recruited, but by what means?

I believe I understand everything that happens after the recruitment of MyD88, but I am less clear on everything before that. I had initially understood that the recruitment of MyD88 was the immediate next step, but other sources make reference to two proteins which I was initially unaware of: TOLLIP and TIRAP. What, if anything, is their role?

I'm still a little new to stackexchange so I apologise if this question is not up to standard, in which case, let the question simply be: 'How do TLR1/TLR2 activate the MyD88 dependent pathway?'

Improve this question
$\endgroup$
1
$\begingroup$

The TLR are usually working as homodimers (Toll-like receptors), although TLR2 can cooperate with TLR1 or 6. Upon binding of its ligand (this is called pathogen associated molecular pattern) the receptors change their conformation and allow binding of TIRAP (TIR adapter protein) to their Toll-interleukin 1 receptor (TIR) domain. TIRAP then recruits MYD88, which then recruits IRAK1 or 4. The signal is then passed down the pathway as shown in the figure below (taken from the Wikipedia article on TLR).

enter image description here

Improve this answer
$\endgroup$
3
  • 1
    $\begingroup$ Pretty good, but a correction - MyD88 recruits both IRAK1 and IRAK4. 4 then gets phosphorylated, and in turn phosphorylates 1 at Thr209 and Thr387. This in turn activates 1's kinase activity, and it hyper-autophosphorylates. 1 (and maybe 4) then dissociates from the complex, becomes ubiquitinated, and goes on to recruit the membrane-bound TAB/TRAF complex, which facilitates activation of TAK and RIP, leading to the NF-kB, PI3K/Akt, and MAPK pathways. $\endgroup$ – MattDMo Mar 5 '14 at 22:08
  • $\begingroup$ Thats correct. I updated the answer. Thanks for it. $\endgroup$ – Chris♦ Mar 5 '14 at 22:13
  • $\begingroup$ I really enjoyed your link but I remain a little confused by sentences such as "Lipopeptides and other components of Gram-positive bacterial cells activate TLR2 in conjunction with either TLR1 or TLR6." Should I understand by this that you either have two TLR1 monomers which, together, form a homodimer, or you have a TLR1 monomer and a TLR2 which, together, form a heterodimer? Also, does dimerization occur only after binding with the ligand? $\endgroup$ – Au101 Mar 5 '14 at 22:25

Your Answer

By clicking “Post Your Answer”, you agree to our terms of service, privacy policy and cookie policy

Not the answer you're looking for? Browse other questions tagged or ask your own question.