Noncovalent Lasso Entanglements are Common in Experimentally Derived Intrinsically Disordered Protein Ensembles and Strongly Influenced by Protein Length and Charge

Noncovalent lasso entanglements are
conformations in which a protein
backbone segment forms a loop closed by noncovalent interactions and
that loop is threaded one or more times by either the N- or C-terminal
segment of the backbone or both. While these entanglements are common
in globular proteins, their presence in intrinsically disordered proteins
or regions (IDPs/IDRs) remains largely unexplored. Here, we examine
whether IDPs/IDRs in their monomeric form populate these conformations
and how sequence length and charge composition influence entanglement
prevalence. Using experimentally derived IDP/IDR ensembles from the
Protein Ensemble Database, we find that 48% (199 of 416) of its entries
contain subpopulations with entangled conformations, with 25% of entries
having conformational ensembles in which 50% or more are entangled.
This includes IDPs such as nuclear pore complex protein Nup153, nonstructural
protein V of Hendra virus, and Eukaryotic initiation factor 4F subunit
p150. Using molecular simulations, we find that (i) entanglements
are most prevalent in weak polyampholytes and polyelectrolytes, and
strong polyampholytes but rare in strong polyelectrolytes; (ii) entanglement
populations increase with IDP length; (iii) entanglement probability
positively correlates with chain compaction; and (iv) most IDPs/IDRs
in the human proteome exhibit entangled conformations. A GO enrichment
analysis reveals that the entanglement probability correlates with
IDP/IDR function and subcellular localization. Thus, these findings
indicate that noncovalent lasso entanglements are a widespread structural
feature of IDPs/IDRs and have the potential to be biologically relevant.