Sequence and structural difference favors a distinct preference of Wnt3a binding with co-receptor LRP6

Abstract

Wnt signaling pathway plays a key role in a wide array of development and physiological processes. Wnt proteins interact with two different co-receptors LRP5/6 and ROR 2, leading to different signal transductions in the cell. Though the Wnt family of proteins has high sequence similarity the specificity for particular co-receptor is not well understood. The choice of pathway is attributed to the binding of Wnt complex to the co-receptor. Our current study is a novel approach using homology modeling, docking, and structural alignment to unravel the structural differences between Wnt3a and Wnt5b binding to LRP6. The conservation of a protruding loop has been identified in Wnt3a protein indicating an enhanced ability of Wnt3a to bind to LRP5/6 against its counter parts. The docking studies have further substantiated the findings. This could potentially help us design and develop novel inhibitors targeting Wnt3a-LRP6 complex in specific tissues or disease states.

Keywords:

• Wnt3a
• Wnt5a
• LRP6

Additional information

Funding

This work was supported by DBT-IYBA [grant number BT/PR9048/MED/97/145/2013], DBT-RGYI, DST [grant number SB/EMEQ-114/2013], ICMR [grant number 90/42/2012-BMS], and UGC [grant number 41-1259/2012 (SR)] grants of the Government of India. We appreciate the funding in the form of CSIR and UGC Fellowships from the Government of India.