Dishevelled localization and function are differentially regulated by structurally distinct sterols

Area of Science:

• Molecular and Cellular Biology
• Biochemistry
• Signal Transduction

Background:

• The Dishevelled (DVL) protein family is crucial for cellular processes like tissue patterning and polarity.
• DVL proteins form complexes at the plasma membrane, and cholesterol binding is essential for this association.
• The precise structural requirements and cellular consequences of DVL-sterol interactions remain largely unknown.

Purpose of the Study:

• To investigate the role of sterol structure in regulating DVL protein activity.
• To determine the cellular impacts of DVL-sterol association under normal and pathological conditions.
• To explore the link between altered sterol homeostasis and DVL signaling pathways.

Main Methods:

• In silico modeling and molecular analyses to assess DVL-sterol binding.
• Experiments to evaluate DVL2 plasma membrane association and nuclear localization.
• Analysis of DVL2 protein-protein interactions and downstream signaling pathway impacts.

Main Results:

• Sterol orientation within the DVL-PDZ domain dictates binding specificity.
• Aberrant sterols disrupt DVL2 membrane association, leading to FoxK2-mediated nuclear import.
• Altered sterol homeostasis selectively impairs DVL2 interactions, affecting multiple signaling cascades.

Conclusions:

• Sterol specificity is a key regulator of DVL protein signaling.
• Intracellular sterol levels directly impact DVL localization and functional activity.
• Aberrant DVL activity may contribute to cellular dysfunction in disorders of sterol metabolism.