The long and winding road of the c-Kit juxtamembrane domain

1. Introduction Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal tumors of the human gastrointestinal tract, and most GISTs express constitutively activated c-Kit oncoproteins.1 Several clinical studies demonstrate that tumors showing mutation in exon 11 (encoding the juxtamembrane domain) respond better than all the other GIST tumoral genotypes. The KIT wild-type sequence folds into a series of β- hairpin structures. The structure, stability and folding of β- hairpin structures has been the object of many studies. Recently, several works reported successful simulations of reversible hairpin folding of different peptides in explicit water at native folding conditions through self-guided molecular dynamics (SGMD) simulations.2 2. Results and Discussion Using SGMD simulations we study the reversible folding events of wild-type and mutated c-Kit JMX domains. The mutations considered were the two-residue deletion Δ559-560 (Fig.1) and the missense point mutation V560G, both known to constitutively activate c-Kit in GISTs. This work aids to support the clinical evidence of a better response to Imatinib, an ATP-competitive TKIs, of KIT exon 11 mutant in comparison with WT receptor and provides the first atomistic description of the output of several clinical studies of GIST treated with Imatinib.