Structure and dynamics of Smoothened SMO a potential target for regulation of the Hedgehog HH signaling pathway

Abstract

Hedgehog (HH) signaling pathway is the cellular pathway for patterning and morphogenesis. newlineIt is controlled by two membrane proteins, the HH receptor Patched1 (PTCH1), a 12-pass newlinetransmembrane (TM) protein, and Smoothened (SMO), a 7-pass transmembrane (TM) signal newlinetransducer. SMO transduces the signal from the extracellular (EC) region to the cytoplasmic newline(CP) region. Binding of HH ligand to PTCH1 receptor allows SMO entry to the primary cilium newline(PC) and activates the downstream signaling process. The malfunctioning of SMO results in newlinemisregulation of the HH signaling pathway, which contributes to birth defects and various cancers. The story has evolved from initial conjectures involving direct communication of PTCH1 newlinewith SMO to indirect communication between the two TM proteins. In the process, some of newlinethe old theories have been discarded in recent literature. However, the underlying mechanism newlineof how PTCH1 controls SMO is still not very clear, and thus constitutes an important area newlineof research. Based on available evidence, the consensus appears to be limited to the assertion newlinethat, driven by HH signaling, PTCH1 regulates the activity of SMO activity through the intermediacy of some small molecules (such as cholesterol). In addition, it appears that the lipid newlinebilayer composition affects SMO orientation and function. In this context, several earlier hypotheses involving the primary role of cholesterol are being disputed. At the same time, several newlineHH pathway inhibitors viz., cyclopamine, taladegib, and vismodegib, which target SMO have newlinebeen reported. Notwithstanding their potential utility in the treatment of cancer, long-term newlineadministration of these drugs was reported to lead to the development of resistance. newlineThe broad aim of my research is to build upon the existing molecular-level understanding of newlinethe functioning of the HH pathway, with a view to facilitate the formulation of newer approaches newlinetowards therapeutic intervention. The focus of my research is to investigate the structure and newlinedomain organization of SMO, which