Systematic simulation of the interactions of pleckstrin homology domains with membranes.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35857458.
- Also identified by DOI 10.1126/sciadv.abn6992 and PMC identifier 9258823.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Pleckstrin homology (PH) domains can recruit proteins to membranes by recognition of phosphatidylinositol phosphate (PIP) lipids. Several family members are linked to diseases including cancer. We report the systematic simulation of the interactions of 100 mammalian PH domains with PIP-containing membranes. The observed PIP interaction hotspots recapitulate crystallographic binding sites and reveal a number of insights: (i) The β1 and β2 strands and their connecting loop constitute the primary PIP interaction site but are typically supplemented by interactions at the β3-β4 and β5-β6 loops; (ii) we reveal exceptional cases such as the Exoc8 PH domain; (iii) PH domains adopt different membrane-bound orientations and induce clustering of anionic lipids; and (iv) beyond family-level insights, our dataset sheds new light on individual PH domains, e.g., by providing molecular detail of secondary PIP binding sites. This work provides a global view of PH domain/membrane association involving multivalent association with anionic lipids.