title: In-silico characterization of the effects of phosphorylated tyrosines 86 and 106 on structure and binding of MAL: insight into hyperinflammatory response to infection by the human malaria parasites.
abstract: The innate immune system uses inflammation to respond to infection of humans by various parasitic organisms and in some individuals can produce a hyperinflammatory response to infection by the human malaria parasites Plasmodium falciparum and vivax, leading to a more severe form of the disease-cerebral malaria (CM). Toll-like receptors (TLRs) 2 and 4 and members of its signaling pathway, including myeloid differentiation primary response protein (MyD88), MyD88 adapter-like protein (MAL) and suppressor of cytokine signaling 1 (SOCS1), are involved in this inflammatory response. A number of studies have suggested a possible role for MAL in developing CM and that modulating the behavior of MAL may prevent such complications. Mutagenesis studies have suggested that MAL becomes active after phosphorylation of tyrosines and the computational studies presented here characterize the possible roles of two tyrosines-Tyr86 and Tyr106-in MAL activity. The effects of phosphorylation on the structure of MAL and on its binding with two binding partners MyD88 and SOCS1 are studied here. The results suggest that phosphorylation of Tyr86 leads to conformational changes in the BB loop of MAL, and this conformational switch forms the interface for binding with MyD88. Similarly, our results suggest that phosphorylation of Tyr106 contributes to the stability of MAL-MyD88 dimer formation, and may form a possible binding site for SOCS1. Thus, our study supports roles for tyrosines 86 and 106 in signaling pathways involving MAL, and hence as potential drug targets against hyperinflammatory response to infection by Plasmodium falciparum and vivax.
authors.affiliation: NUST Center of Virology & Immunology, National University of Sciences and Technology, Islamabad, Pakistan. umar-ncvi@nust.edu.pk
authors.forename: Umar H K
authors.initials: UH
authors.lastname: Niazi
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Bibby
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sutcliffe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019295:Computational Biology / Q000379:methods*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000469:parasitology*; D008288:Malaria / Q000378:metabolism / Q000469:parasitology*; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010271:Parasites / Q000502:physiology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D010961:Plasmodium / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017472:Receptors, Interleukin-1 / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D055672:Static Electricity; D013329:Structure-Activity Relationship; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry
chemical_list: D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C434984:TIRAP protein, human; D019000:Phosphotyrosine