Conclusion
In this study, a common putative feature of BLK has been analysed
extensively using bioinformatics tools. BLK is majorly chargeable for
the formation of B-Lymphocytes. It has been observed that human BLK in
its lively shape is an oncogene with the potential aid in terms of
growth of lymphoid cells in vitro and promotes tumour boom in vivo, thus
BLK can be considered to be a capacity novel therapeutic target for
Cutaneous T-cellular lymphoma. The antibody-mediated surface interaction
of the B-cell antigen receptor (BCR) leads to phosphorylation of BLK on
tyrosine amino acids, shows the enzymatic activity. We have modelled the
structure and did the various analysis of BLK structures which will add
the knowledge for understanding the BLK’s functionality in our human
body and its regular development. This study would not only help
pharmacologists to develop new drugs but also to bioinformaticians in
developing new inhibitor to regulate its expression. Till date, the
crystallised structure of BLK is not available hence our modelled
structure followed by structure refinement using MD simulation gives a
stable structure that can be used in pharmacology.
Competing interest
The authors declare that there is no conflict of interest in the
publication of this manuscript.
References
Akerblad, P., & Sigvardsson, M.
(1999). Early B cell factor is an activator of the B lymphoid kinase
promoter in early B cell development. J Immunol, 163 (10),
5453-5461.
Bewarder, N., Weinrich, V., Budde, P.,
Hartmann, D., Flaswinkel, H., Reth, M., & Frey, J. (1996). In vivo and
in vitro specificity of protein tyrosine kinases for immunoglobulin G
receptor (FcgammaRII) phosphorylation. Mol Cell Biol, 16 (9),
4735-4743.
Bhattacharya, D., & Cheng, J. (2013). i3Drefine software for protein 3D
structure refinement and its assessment in CASP10. PloS
one , 8 (7).
Borowiec, M., Liew, C. W., Thompson,
R., Boonyasrisawat, W., Hu, J., Mlynarski, W. M., . . . Doria, A.
(2009). Mutations at the BLK locus linked to maturity onset diabetes of
the young and beta-cell dysfunction. Proc Natl Acad Sci U S A,
106 (34), 14460-14465.
Castillejo-López, C., Delgado-Vega, A.
M., Wojcik, J., Kozyrev, S. V., Thavathiru, E., Wu, Y.-Y., . . .
Fineschi, S. (2012). Genetic and physical interaction of the B-cell
systemic lupus erythematosus-associated genes BANK1 and BLK.Annals of the rheumatic diseases, 71 (1), 136-142.
Clark, M. R., Mandal, M., Ochiai, K.,
& Singh, H. (2014). Orchestrating B cell lymphopoiesis through
interplay of IL-7 receptor and pre-B cell receptor signalling.Nature reviews Immunology, 14(2), 69-80.
Craig, M. E., Hattersley, A., &
Donaghue, K. C. (2009). Definition, epidemiology and classification of
diabetes in children and adolescents. Pediatric
diabetes , 10 , 3-12.
Dai, F. F., Bhattacharjee, A., Liu,
Y., Batchuluun, B., Zhang, M., Wang, X. S., … & Wheeler, M. B.
(2015). A novel GLP1 receptor interacting protein ATP6ap2 regulates
insulin secretion in pancreatic beta cells. Journal of Biological
Chemistry , 290 (41), 25045-25061.
Dymecki, S. M., Niederhuber, J. E., &
Desiderio, S. V. (1990). Specific expression of a tyrosine kinase gene,
blk, in B lymphoid cells. Science , 247 (4940), 332-336.
Dymecki, S. M., Zwollo, P., Zeller,
K., Kuhajda, F. P., & Desiderio, S. V. (1992). Structure and
developmental regulation of the B-lymphoid tyrosine kinase gene
blk. Journal of Biological Chemistry , 267 (7), 4815-4823.
El-Gebali, S., Mistry, J., Bateman,
A., Eddy, S. R., Luciani, A., Potter, S. C., … & Sonnhammer, E. L. L.
(2019). The Pfam protein families database in 2019. Nucleic acids
research , 47 (D1), D427-D432.
Fishilevich, S., Zimmerman, S., Kohn,
A., Iny Stein, T., Olender, T., Kolker, E., . . . Lancet, D. (2016).
Genic insights from integrated human proteomics in GeneCards.Database, 2016 .
Garnier, J., Osguthorpe, D. J., &
Robson, B. (1978). Analysis of the accuracy and implications of simple
methods for predicting the secondary structure of globular
proteins. Journal of molecular biology , 120 (1), 97-120.
Gasteiger, E., Hoogland, C.,
Gattiker, A., Wilkins, M. R., Appel, R. D., & Bairoch, A. (2005).
Protein identification and analysis tools on the ExPASy server. InThe proteomics protocols handbook (pp. 571-607): Springer.
Gupta, R., Jung, E., & Brubak, S.
(2004). NetNGlyc: prediction of N-glycosylation sites in human proteins.
In: Prep.
Halgren, T. A. (2009). Identifying
and characterizing binding sites and assessing
druggability. Journal of chemical information and
modeling , 49 (2), 377-389.
Harley, J. B., Alarcón-Riquelme, M.
E., Criswell, L. A., Jacob, C. O., Kimberly, R. P., Moser, K. L., . . .
Genetics, I. C. f. S. L. E. (2008). Genome-wide association scan in
women with systemic lupus erythematosus identifies susceptibility
variants in ITGAM, PXK, KIAA1542 and other loci. Nature genetics,
40 (2), 204.
Holbrook, N. J., Smith, K. A.,
Fornace, A. J., Comeau, C. M., Wiskocil, R. L., & Crabtree, G. R.
(1984). T-cell growth factor: complete nucleotide sequence and
organization of the gene in normal and malignant
cells. Proceedings of the National Academy of
Sciences , 81 (6), 1634-1638.
Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: visual molecular
dynamics. Journal of molecular graphics , 14 (1), 33-38.
Jacobson, M. P., Pincus, D. L., Rapp,
C. S., Day, T. J., Honig, B., Shaw, D. E., & Friesner, R. A. (2004). A
hierarchical approach to all‐atom protein loop
prediction. Proteins: Structure, Function, and
Bioinformatics , 55 (2), 351-367.
JADWIN, J. A. (2017). Quantitative
Analysis of EGFR Phosphorylation and SH2 Domain Binding in vivo.Doctoral Dissertations , 1437, University of Connecticut Graduate
School.
Kaul, T., Eswaran, M., Ahmad, S.,
Thangaraj, A., Jain, R., Kaul, R., … & Bharti, J. (2019). Probing the
effect of a plus 1bp frameshift mutation in protein-DNA interface of
domestication gene, NAMB1, in wheat. Journal of Biomolecular
Structure and Dynamics , 1-15.
Kurosaki, T. (2002). Regulation of
B-cell signal transduction by adaptor proteins. Nature Reviews
Immunology , 2 (5), 354-363.
Letunic, I., & Bork, P. (2019).
Interactive Tree Of Life (iTOL) v4: recent updates and new
developments. Nucleic acids research , 47 (W1), W256-W259.
Liu, H., Zhang, H., Wu, X., Ma, D.,
Wu, J., Wang, L., . . . Ge, B. (2018). Nuclear cGAS suppresses DNA
repair and promotes tumorigenesis. Nature, 563 (7729), 131-136.
Malek, S. N., Dordai, D. I., Reim,
J., Dintzis, H., & Desiderio, S. (1998). Malignant transformation of
early lymphoid progenitors in mice expressing an activated Blk tyrosine
kinase. Proceedings of the National Academy of Sciences, 95 (13),
7351-7356.
Murata, K., Ishii, N., Takano, H.,
Miura, S., Ndhlovu, L. C., Nose, M., . . . Sugamura, K. (2000).
Impairment of antigen-presenting cell function in mice lacking
expression of OX40 ligand. The Journal of experimental medicine,
191 (2), 365-374.
Oda, H., Kumar, S., & Howley, P. M.
(1999). Regulation of the Src family tyrosine kinase Blk through
E6AP-mediated ubiquitination. Proc Natl Acad Sci U S A, 96 (17),
9557-9562.
Petersen, D. L., Berthelsen, J.,
Willerslev-Olsen, A., Fredholm, S., Dabelsteen, S., Bonefeld, C. M., . .
. Woetmann, A. (2017). A novel BLK-induced tumor model. Tumour
Biol, 39 (7), 1010428317714196.
Ramírez-Bello, J., Jiménez-Morales,
S., Montufar-Robles, I., Fragoso, J. M., Barbosa-Cobos, R. E., Saavedra,
M. A., & Sánchez-Muñoz, F. (2019). BLK and BANK1 polymorphisms and
interactions are associated in Mexican patients with systemic lupus
erythematosus. Inflammation Research, 68 (8), 705-713.
Rice, P., Longden, I., & Bleasby, A. (2000). EMBOSS: the European
Molecular Biology Open Software Suite. Trends in genetics:
TIG , 16 (6), 276-277.
Rozewicki, J., Li, S., Amada, K. M.,
Standley, D. M., & Katoh, K. (2019). MAFFT-DASH: integrated protein
sequence and structural alignment. Nucleic acids
research , 47 (W1), W5-W10.
Schisler, J. C., Jensen, P. B.,
Taylor, D. G., Becker, T. C., Knop, F. K., Takekawa, S., … & Newgard,
C. B. (2005). The Nkx6. 1 homeodomain transcription factor suppresses
glucagon expression and regulates glucose-stimulated insulin secretion
in islet beta cells. Proceedings of the National Academy of
Sciences , 102 (20), 7297-7302.
Schrödinger, L. (2016). Schrödinger Suite. Schrödinger, LLC, New
York, NY .
Sharma, R. B., O’Donnell, A. C.,
Stamateris, R. E., Ha, B., McCloskey, K. M., Reynolds, P. R., … &
Alonso, L. C. (2015). Insulin demand regulates β cell number via the
unfolded protein response. The Journal of clinical
investigation , 125 (10), 3831-3846.
Shen, Y., Liu, Y., Wang, X. Q., Ke,
X., Kang, H. Y., & Hong, S. L. (2017). Association between TNFSF4 and
BLK gene polymorphisms and susceptibility to allergic rhinitis.Molecular medicine reports, 16 (3), 3224-3232.
Singh, T., Biswas, D., & Jayaram, B.
(2011). AADS-An automated active site identification, docking, and
scoring protocol for protein targets based on physicochemical
descriptors. Journal of chemical information and
modeling , 51 (10), 2515-2527.
Sliwoski, G., Kothiwale, S., Meiler,
J., & Lowe, E. W. (2014). Computational methods in drug
discovery. Pharmacological reviews , 66 (1), 334-395.
Stelzer, G., Rosen, N., Plaschkes,
I., Zimmerman, S., Twik, M., Fishilevich, S., … & Kaplan, S. (2016).
The GeneCards suite: from gene data mining to disease genome sequence
analyses. Current protocols in bioinformatics , 54 (1),
1-30.
Summy, J. M., & Gallick, G. E.
(2003). Src family kinases in tumor progression and metastasis.Cancer and metastasis reviews, 22 (4), 337-358.
Tretter, T., Ross, A. E., Dordai, D.
I., & Desiderio, S. (2003). Mimicry of pre-B cell receptor signaling by
activation of the tyrosine kinase Blk. J Exp Med, 198 (12),
1863-1873.
Wass, M. N., Kelley, L. A., &
Sternberg, M. J. (2010). 3DLigandSite: predicting ligand-binding sites
using similar structures. Nucleic acids
research , 38 (suppl_2), W469-W473.
Waterhouse, A., Bertoni, M., Bienert,
S., Studer, G., Tauriello, G., Gumienny, R., … & Lepore, R. (2018).
SWISS-MODEL: homology modelling of protein structures and
complexes. Nucleic acids research , 46 (W1), W296-W303.