A structural screen for candidate polyphosphate binding surfaces in human membrane associated proteins
- 1Queen's University
Abstract
Inorganic polyphosphate (polyP) can alter protein function through noncovalent binding, yet its partners among human membrane associated proteins remain poorly characterized. PolyP is recognized through two modes: a structure-based mode driven by charge complementarity with sites assembled by protein folding, and a more recently defined sequence-based mode at histidine and lysine rich tracts. The sequence determinant is well defined and directly searchable; the structure-based mode has few characterized examples and no systematic search method, because its residues leave no contiguous sequence signature. Broad experimental binding screens are especially demanding for integral membrane proteins, which require specialized conditions. We therefore developed a computational workflow that searches predicted structures for surfaces able to accommodate a phosphate chain. We designed custom scores that integrate surface electrostatics, docking results and structural confidence to prioritize candidates. From 19,481 completed docking searches on 5,648 AlphaFold models representing 2,925 UniProt protein entries, we nominated 82 entries as candidates for noncovalent polyP binding. Predicted polyP contacts in 18 candidate entries overlapped experimentally characterized functional residues, linking the predicted interfaces to established sites of ligand recognition, regulation and membrane attachment. The workflow ranks computational results rather than measuring binding, providing specific targets for experimental investigation.
Related
- Single Molecule Diffusion Studies Reveal Rapid Translations Across Target Membrane Surfaces for both p40Phox PX domain and Class III PI3K VPS34 Complex 1, the Autophagy Lipid Kinase
- Preparation of Phosphoinositide-Containing Supported Lipid Bilayers and Quantitative Assessment of Protein Recruitment to Membrane Surfaces.
- Long-read genome assembly of high-erucic-acid Brassica napus reveals candidate structural variants in fatty acid metabolism genes
- Structural basis of selective phospholipid recognition and local membrane deformation by CTL1
- Inositol hexakisphosphate kinase 1 regulates polyphosphate synthesis by maintaining V-ATPase-dependent secretory granule acidification
BibTeX
@misc{wu2026structural,
title = {{A structural screen for candidate polyphosphate binding surfaces in human membrane associated proteins}},
author = {J. Wu and Z. Jia},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.25.761654},
url = {https://www.biorxiv.org/content/10.64898/2026.10.25.761654v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - A structural screen for candidate polyphosphate binding surfaces in human membrane associated proteins
AU - J. Wu
AU - Z. Jia
PY - 2026
DA - 2026/10/25
PB - bioRxiv
DO - 10.64898/2026.10.25.761654
UR - https://www.biorxiv.org/content/10.64898/2026.10.25.761654v1
AB - Inorganic polyphosphate (polyP) can alter protein function through noncovalent binding, yet its partners among human membrane associated proteins remain poorly characterized. PolyP is recognized through two modes: a structure-based mode driven by charge complementarity with sites assembled by protein folding, and a more recently defined sequence-based mode at histidine and lysine rich tracts. The sequence determinant is well defined and directly searchable; the structure-based mode has few characterized examples and no systematic search method, because its residues leave no contiguous sequence signature. Broad experimental binding screens are especially demanding for integral membrane proteins, which require specialized conditions. We therefore developed a computational workflow that searches predicted structures for surfaces able to accommodate a phosphate chain. We designed custom scores that integrate surface electrostatics, docking results and structural confidence to prioritize candidates. From 19,481 completed docking searches on 5,648 AlphaFold models representing 2,925 UniProt protein entries, we nominated 82 entries as candidates for noncovalent polyP binding. Predicted polyP contacts in 18 candidate entries overlapped experimentally characterized functional residues, linking the predicted interfaces to established sites of ligand recognition, regulation and membrane attachment. The workflow ranks computational results rather than measuring binding, providing specific targets for experimental investigation.
ER -