A new in-silico method for determination of helical transmembrane domains based on the PepLook scan: application to IL-2Rβ and IL-2Rγc receptor chains

Using sequences whose NMR-structures are already known (GpA, EphA1 and Erb2-HER2), we first determined that the hydrophobic to hydrophilic accessible surface area ratio (ASAr) was the best criterion for delimiting the TMD sequence. The length of the helical structure and the Impala method further supported the determination of the TMD limits. This method was applied to the IL-2Rβ and IL-2Rγ TMD sequences of Homo sapiens, Rattus norvegicus, Mus musculus and Bos taurus.We succeeded in reducing the variation in the TMD limits to only 2 residues and in gaining structural information.IL-2 and IL-15 are two structurally close hematopoietic cytokines, both presenting a functional redundancy and both involved in immunology and inflammatory diseases. IL-2 was implicated in the first metastatic melanoma immunotherapy [1] and is used in adoptive immunotherapy with tumor infiltrating lymphocytes (TILs). Most treatments require high doses of IL-2 [2,3] and induce a systemic toxicity similar to GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor) treatments [4]. These secondary effects restrict the therapy and have led to investigations into other forms of treatment, such as the promising IL-15 therapy.Transduction receptor chains IL-2Rβ and IL-2Rγc (class I hematopoietic receptors) form an intermediate-affinity complex capable of binding IL-2 and IL-15. Whereas the IL-2Rβ chain is restricted to dimeric receptor for IL-15 and IL-2 [5] or to specific trimeric receptors (IL-2Rβ/IL-2Rγ/IL-2Rα and IL-2Rβ/IL-2Rγ/IL-15Rα), the IL-2Rγc chain is involved in γc-family receptors, that is to say the IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 and GM-CSF receptors[6]. γc-deficit is implicated in immunodeficiency, such as X-linked Severe Combined ImmunoDeficiency (X-SCID)[7].Fluorescence resonance energy transfer (FRET) studies suggest that IL-2Rα, IL-7Rα and IL-15Rα chains are co-localized[8] with IL-2Rβ and γc chains within lipid rafts[9]. IL-2Rα and IL-15Rα chains also appear to co-localize