Abstract
The clustering of proteins and lipids in distinct microdomains is emerging as an important principle for the spatial patterning of biological membranes. Such domain formation can be the result of hydrophobic and ionic interactions with membrane lipids as well as of specific protein–protein interactions. Here using plasma membrane-resident SNARE proteins as model, we show that hydrophobic mismatch between the length of transmembrane domains (TMDs) and the thickness of the lipid membrane suffices to induce clustering of proteins. Even when the TMDs differ in length by only a single residue, hydrophobic mismatch can segregate structurally closely homologous membrane proteins in distinct membrane domains. Domain formation is further fine-tuned by interactions with polyanionic phosphoinositides and homo and heterotypic protein interactions. Our findings demonstrate that hydrophobic mismatch contributes to the structural organization of membranes.
Highlights
The clustering of proteins and lipids in distinct microdomains is emerging as an important principle for the spatial patterning of biological membranes
We show that hydrophobic mismatch between the length of transmembrane domains (TMDs) and the thickness of the plasma membrane contributes to the clustering of proteins in the plasma membrane
We show that hydrophobic mismatch can contribute to the segregation of structurally closely homologous SNARE proteins in distinct membrane domains even when the TMDs differ in length by only a single residue
Summary
The clustering of proteins and lipids in distinct microdomains is emerging as an important principle for the spatial patterning of biological membranes. The physical principles underlying cluster formation within the bilayer are still unclear, with explanations including mechanisms as diverse as phase partitioning into cholesterol-enriched membrane rafts[5,19,20,21], decreased solubility caused by the presence of cholesterol[15,16], electrostatic interactions with the phosphoinositides[10,18], and homophilic as well as heterophilic interactions between the proteins themselves involving either the hydrophobic TMDs or the hydrophilic domains[8,9,22]. We show that hydrophobic mismatch can contribute to the segregation of structurally closely homologous SNARE proteins in distinct membrane domains even when the TMDs differ in length by only a single residue
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