Fuzzy Association of an Intrinsically Disordered Protein with Acidic Membranes

Many physiological and pathophysiological processes, including Mycobacterium tuberculosis (Mtb) cell division, may involve fuzzy membrane association by proteins via intrinsically disordered regions. The fuzziness is extreme when the conformation and pose of the bound protein and the composition of the proximal lipids are all highly dynamic. Here, we tackled the challenge in characterizing the extreme fuzzy membrane association of the disordered, cytoplasmic N-terminal region (NT) of ChiZ, an Mtb divisome protein, by combining solution and solid-state NMR spectroscopy and molecular dynamics simulations. While membrane-associated NT does not gain any secondary structure, its interactions with lipids are not random, but formed largely by Arg residues predominantly in the second, conserved half of the NT sequence. As NT frolics on the membrane, lipids quickly redistribute, with acidic lipids, relative to zwitterionic lipids, preferentially taking up Arg-proximal positions. The asymmetric engagement of NT arises partly from competition between acidic lipids and acidic residues, all in the first half of NT, for Arg interactions. This asymmetry is accentuated by membrane insertion of the downstream transmembrane helix. This type of semispecific molecular recognition may be a general mechanism by which disordered proteins target membranes.

Automated summary

Many physiological and pathophysiological processes may involve fuzzy membrane association by proteins via intrinsically disordered regions. This study tackled the extreme fuzzy membrane association of the disordered, cytoplasmic N-terminal region (NT) of an Mtb divisome protein using a combination of solution and solid-state NMR spectroscopy and molecular dynamics simulations. The interactions between the membrane-associated NT and lipids are largely formed by Arg residues, with a preference for acidic lipids in close proximity to these residues.