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Letter To Editor
2008:74:3;272-273
doi: 10.4103/0378-6323.41386
PMID: 18583808

ErbB2: Nonimmune genetic key to leprosy

Bell Raj Eapen
 Specialist Dermatologist, Kaya Skin Clinic, Dubai, United Arab Emirates

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
Copyright: (C)2008 Indian Journal of Dermatology, Venereology, and Leprology

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.

References
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