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ErbB2: Nonimmune genetic key to leprosy
Correspondence Address:
Bell Raj Eapen
Kaya Skin Clinic, Dubai
United Arab Emirates
| How to cite this article: Eapen BR. ErbB2: Nonimmune genetic key to leprosy. Indian J Dermatol Venereol Leprol 2008;74:272-273 |
Sir,
I read with interest, the article titled "Ligand-binding prediction for ErbB2, a key molecule in the pathogenesis of leprosy" in the January 2008 issue of IJDVL. [1] It illustrates the growing importance of structural bioinformatics in clinical medicine and drug discovery. However, the use of the term ′ligand′ in place of ′ligand-binding site′ in the article could be misleading. A ligand is a molecule that is able to bind to and form a complex with a biomolecule to serve a biological purpose. Bioinformatics tools like Q-Site finder [2] predict putative binding sites within biomolecular structures after excluding bound ligands. ErbB2 has no known ligands [3] (unlike other ErbB receptors) and signalling is mediated through heterodimerization with ErbB3 or homodimerization with another ErbB2 (proposed mechanism of signalling in leprosy). [4] Docking studies and virtual high-throughput screening techniques are needed to identify unknown ligands (potential drug candidates) for ErbB2. [5]
Only extracellular Mycobacterium Leprae utilizes ErbB2 for downstream extracellular signal-regulated kinase (ERK) activation. [6] In contrast, lymphoid cell kinase (p56Lck) has been found to activate ERK 1/2 directly through a PKC e-dependent (Protein Kinase C e), MEK-independent (MEK = MAPK/Erk kinase; MAPK = Mitogen-activated protein kinase) pathway in intracellular Mycobacterium leprae . [7] Hence, ErbB2 inhibitors are unlikely to have a huge impact on leprosy therapeutics.
ErbB2 is a membrane protein with an extracellular region comprised of four domains, a single transmembrane helix and an intracellular region with a tyrosine kinase domain. [8] The structure (PDB: 2A91) used in the study, is a truncated one with three domains and 510 residues. [9] The structure of the entire extracellular region of ErbB2 bound to herceptin is available in PDB: 1N8Z. [10]
There is strong epidemiological evidence that genetic factors influence susceptibility to leprosy per se and to the leprosy type. Majority of the genes implicated in susceptibility to leprosy are immunity-related such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-10. [11] A recent study of the spatial structure of the transmembrane domains of dimerized ErbB2 identified certain single-nucleotide polymorphisms (SNPs) which can excessively stabilize dimeric ErbB2 leading to spontaneous signalling. [12] Although the obvious relevance is its oncogenic potential, the possibility of a similar nonimmune mechanism that increases the susceptibility to leprosy, cannot be overlooked.
| 1. |
Wiwanitkit V. Ligand-binding prediction for ErbB2, a key molecule in the pathogenesis of leprosy. Indian J Dermatol Venereol Leprol 2008;74:32-4.
[Google Scholar]
|
| 2. |
Laurie AT, Jackson RM. Q-SiteFinder: An energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 2005;21:1908-916.
[Google Scholar]
|
| 3. |
Yarden Y. The EGFR family and its ligands in human cancer signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001;37:S3-8.
[Google Scholar]
|
| 4. |
Tapinos N, Ohnishi M, Rambukkana A. ErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilli. Nat Med 2006;12:961-6.
[Google Scholar]
|
| 5. |
Taylor P, Blackburn E, Sheng YG, Harding S, Hsin KY, Kan D et al. Ligand discovery and virtual screening using the program LIDAEUS. Br J Pharmacol 2007;152:S55-67.
[Google Scholar]
|
| 6. |
Noon LA, Lloyd AC. Treating leprosy: An Erb-al remedy? Trends Pharmacol Sci 2007;28:103-5.
[Google Scholar]
|
| 7. |
Tapinos N, Rambukkana A. Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli. Proc Natl Acad Sci USA 2005;102:9188-93.
[Google Scholar]
|
| 8. |
Bagossi P, Horvath G, Vereb G, Szollosi J, Tozser J. Molecular modeling of nearly full-length ErbB2 receptor. Biophys J 2005;88:1354-63.
[Google Scholar]
|
| 9. |
Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 2003;11:495-505.
[Google Scholar]
|
| 10. |
Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003;421:756-60.
[Google Scholar]
|
| 11. |
Moraes MO, Cardoso CC, Vanderborght PR, Pacheco AG. Genetics of host response in leprosy. Lepr Rev 2006;77:189-202.
[Google Scholar]
|
| 12. |
Bocharov EV, Mineev KS, Volynsky PE, Ermolyuk YS, Tkach EN, Sobol AG, et al. Spatial structure of dimeric transmembrane domain of the growth factor receptor ErbB2 presumably corresponding to the receptor active state. J Biol Chem 2008;283:6950-6.
[Google Scholar]
|
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