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Structural evaluation of BTK and PKCδ mediated phosphorylation of MAL at positions Tyr86 and Tyr106

Paper ID Volume ID Publish Year Pages File Format Full-Text
15117 1379 2014 14 PDF Available
Title
Structural evaluation of BTK and PKCδ mediated phosphorylation of MAL at positions Tyr86 and Tyr106
Abstract

•Protein docking indicated that BTK bind within region of Tyr86 and Tyr106 of MAL.•Protein docking indicated that PKCd bind within region of Tyr106 of MAL only.•Charge distribution on surface of BTK and PKCd were distinct.•Competitive action of both BTK and PKCd is present at site of Tyr106.•Residues of MAL interact with other TIR domains are also involved with kinases.

A number of diseases including sepsis, rheumatoid arthritis, diabetes, cardiovascular diseases and hyperinflammatory immune disorders have been associated with Toll like receptor (TLR) 2 and TLR4. Endogenous adaptor protein known as MyD88 adapter-like protein (MAL) bind exclusively to the cytosolic portions of TLR2 and TLR4 to initiate downstream signalling. Brutons tyrosine kinase (BTK) and protein kinase C delta (PKCδ) have been implicated to phosphorylate MAL and activate it to initiate downstream signalling. BTK has been associated with phosphorylation at positions Tyr86 and Tyr106, necessary for the activation of MAL but definite residual target of PKCδ in MAL is still to be explored. To produce a better understanding of the functional domains involved in the formation of MAL–kinase complexes, computer-aided studies were used to characterize the protein–protein interactions (PPIs) of phosphorylated BTK and PKCδ with MAL. Docking and physicochemical studies indicated that BTK was involved in close contact with Tyr86 and Tyr106 of MAL whereas PKCδ may phosphorylate Tyr106 only. Moreover, the electrostatics charge distribution of binding interfaces of BTK and PKCδ were distinct but compatible with respective regions of MAL. Our results implicate that position of Tyr86 is specifically phosphorylated by BTK whereas Tyr106 can be phosphorylated by competitive action of both BTK and PKCδ. Additionally, the residues of MAL which are necessary for interaction with TLR2, TLR4, MyD88 and SOCS-1 also play their roles in maintaining interaction with kinases and can be targeted in future to reduce TLR2 and TLR4 induced pathological responses.

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Keywords
MAL; TIRAP; BTK; PKCδ; Protein–protein interactions (PPIs); Tyr86; Tyr106; Adenosine triphosphate (ATP)
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Structural evaluation of BTK and PKCδ mediated phosphorylation of MAL at positions Tyr86 and Tyr106
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Publisher
Database: Elsevier - ScienceDirect
Journal: Computational Biology and Chemistry - Volume 51, August 2014, Pages 22–35
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us