Structural evaluation of BTK and PKCδ mediated phosphorylation of MAL at positions Tyr86 and Tyr106.
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.
Atta-Ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan.
Rehan Zafar
RZ
Paracha
Atta-Ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan. Electronic address: amjad_uni@yahoo.com.
Amjad
A
Ali
Research Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan. Electronic address: jamil.ahmad@rcms.nust.edu.pk.
Jamil
J
Ahmad
Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad 44000, Pakistan.
Riaz
R
Hussain
IBERS, Aberystwyth University, Edward Llwyd Building, Penglais Campus, Aberystwyth, Ceredigion, Wales SY23 3FG, UK.
Umar
U
Niazi
Department of Pharmacy, COMSATS Institute of Information Technology Abbottabad, 22060, Pakistan.
Syed Aun
SA
Muhammad
D000077329:Agammaglobulinaemia Tyrosine Kinase; D020816:Amino Acid Motifs; D001665:Binding Sites; D005786:Gene Expression Regulation; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051745:Protein Kinase C-delta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D055672:Static Electricity; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D051195:Toll-Like Receptor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry* / Q000378:metabolism
C569026:MAL protein, human; C507779:MYD88 protein, human; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D051745:Protein Kinase C-delta
Adenosine triphosphate (ATP); BTK; MAL; PKCδ; Protein–protein interactions (PPIs); TIRAP; Tyr106; Tyr86