Computer modeling of the membrane interaction of FYVE domains.
FYVE domains are membrane targeting domains that are found in proteins involved in endosomal trafficking and signal transduction pathways. Most FYVE domains bind specifically to phosphatidylinositol 3-phosphate (PI(3)P), a lipid that resides mainly in endosomal membranes. Though the specific interactions between FYVE domains and the headgroup of PI(3)P have been well characterized, principally through structural studies, the available experimental structures suggest several different models for FYVE/membrane association. Thus, the manner in which FYVE domains adsorb to the membrane surface remains to be elucidated. Towards this end, recent experiments have shown that FYVE domains bind PI(3)P in the context of phospholipid bilayers and that hydrophobic residues on a conserved loop are able to penetrate the membrane interface in a PI(3)P-dependent manner.Here, the finite difference Poisson-Boltzmann (FDPB) method has been used to calculate the energetic interactions of FYVE domains with phospholipid membranes. Based on the computational analysis, it is found that (1) recruitment to membranes is facilitated by non-specific electrostatic interactions that occur between basic residues on the domains and acidic phospholipids in the membrane, (2) the energetic analysis can quantitatively differentiate among the modes of membrane association proposed by the experimentally determined structures, (3) FDPB calculations predict energetically feasible models for the membrane-associated states of FYVE domains, (4) these models are consistent with the observation that conserved hydrophobic residues insert into the membrane interface, and (5) the calculations provide a molecular model for the hydrophobic partitioning: binding of PI(3)P significantly neutralizes positive potential in the region of the hydrophobic residues, which acts as an "electrostatic switch" by reducing the energetic barrier for membrane penetration. Finally, the computational results are extended to FYVE domains of unknown structure through the construction of high quality homology models for human FYVE sequences.
Diraviyam
Karthikeyan
K
Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Box 62, New York, NY 10021, USA.
Stahelin
Robert V
RV
Cho
Wonhwa
W
Murray
Diana
D
D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D056827:Endosomal Sorting Complexes Required for Transport; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010743:Phospholipids; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D040681:Structural Homology, Protein; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; D010743:Phospholipids; D010750:Phosphoproteins; D029701:Saccharomyces cerevisiae Proteins; C119627:VPS27 protein, S cerevisiae; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C055525:phosphatidylinositol 3-phosphate