Characterization of All Possible Single-Nucleotide Change Caused Amino Acid Substitutions in the Kinase Domain of Bruton Tyrosine Kinase

Abstract

Knowledge about features distinguishing deleterious and neutral variations is crucial for interpretation of novel variants. Bruton tyrosine kinase (BTK) contains the highest number of unique disease-causing variations among the human protein kinases, still it is just 10% of all the possible single-nucleotide substitution-caused amino acid variations (SNAVs). In the BTK kinase domain (BTK-KD) can appear altogether 1,495 SNAVs. We investigated them all with bioinformatic and protein structure analysis methods. Most disease-causing variations affect conserved and buried residues disturbing protein stability. Minority of exposed residues is conserved, but strongly tied to pathogenicity. Sixty-seven percent of variations are predicted to be harmful. In 39% of the residues, all the variants are likely harmful, whereas in 10% of sites, all the substitutions are tolerated. Results indicate the importance of the entire kinase domain, involvement in numerous interactions, and intricate functional regulation by conformational change. These results can be extended to other protein kinases and organisms.

Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant

“…4, 5, 6 Loss-of-function variations of BTK cause X-linked agammaglobulinemia (XLA) in humans. 7, 8, 9, 10, 11, 12 BTK is a multi-domain protein of 659 amino acids, consisting of N-terminal Pleckstrin homology (PH) and Tec homology (TH) domains, followed by Src homology 3 (SH3), 2 (SH2) and C-terminal catalytic (SH1) domains. 1, 2, 3 …”

Phyto-Medicine in Gene(s) Targeting Future Direction for Sickle Cell Disease Management

“…Biochemically, SCD occurs due to a non-conservative substitution of a polar glutamate (Glu) by non-polar valine (Val) in an invariant region, the sixth position of Hb-β chain-subunit (GAG/GTG; Glu (E) [6] Val (V); rs334) [5][6][7]. Replacement of this single non-polar amino acid 'valine' results in a biochemical difference that leads to formation of a sticky patch on the surface of the β-chains.…”

“…Due to oxygen deprivation in the RBC, a critical aggregate of Hb polymer is formed that damages the cellular membrane, promoting aggregation of cellular proteins, stopping the flow of blood in the narrow capillaries and leading to localized oxygen deprivation (anoxia) [5,7,8]. This polymerization is enhanced by the heterogeneous nature of the nucleus, where new polymers are continually formed on preexisting polymer to form a fourteen inter-wined helical strands of HbS.…”

“…This polymerization is enhanced by the heterogeneous nature of the nucleus, where new polymers are continually formed on preexisting polymer to form a fourteen inter-wined helical strands of HbS. In each molecule, one of the two β6 Valines of the α2 β2 tetramer is involved in an intermolecular contact with its neighbour in the double strand [7,8]. Formation of deoxy-HbS polymer makes the Hb insoluble, change the biconcave structure of the red blood cells and eventually cause cell lysis, which leads to the various clinical features of SCD [5].…”

“…Formation of deoxy-HbS polymer makes the Hb insoluble, change the biconcave structure of the red blood cells and eventually cause cell lysis, which leads to the various clinical features of SCD [5]. Hydrops fetalis, hemolytic [5] anemia, splenomegaly [5] β South Asia, Mediterranean, Africa Transfusion dependent [5] Keys: A.A= Amino Acids, E>V= Glutamate to Valine, E>K= Glutamate to Lysine It is known that amino acid variations have very large diverse effects affecting protein sequence, structure, stability, interactions, activity, abundance and other properties, such as shape, pKa and pH [7,9,10].…”