Structural basis of wedging the Golgi membrane by FAPP pleckstrin homology domains

Abstract

Structural basis of wedging the Golgi membrane by FAPP pleckstrin homology domainsOverduin and colleagues present the NMR structures of free, micelle and PtdIns(4)P-bound FAPP1-PH domain. The micelle-bound structure reveals how its prominent wedge independently tubulates Golgi membranes by leaflet penetration. A hydrophobic element inserts into and bends membranes, and is conserved in pleckstrin homology domains of CERT and OSBP proteins.

Structural Basis for the Golgi Association by the Pleckstrin Homology Domain of the Ceramide Trafficking Protein (CERT)

“…The ␤1/␤2 loop of the PH domain reportedly penetrates into the membrane (36). The binding mode of the FAPP1 PH domain is consistent with our binding model, as the ␤1/␤2 loop of the CERT PH domain should be buried in the membrane (Fig.…”

“…All of the COFs family proteins specifically recognize PtdIns(4)P and target the Golgi in a PtdIns(4)P-dependent manner (4, 27, 39, 40, 44 -46). In addition, the binding mode of all of the COFs family PH domains are similar to that of the CERT PH domain, as characterized the weak affinities to the headgroup of PtdIns(4)P (the K D values are millimolar range or even undetected) and significant affinities to the PtdIns(4)P-embedded Golgi-mimetic liposomes (the K D values are 0.3ϳ3 M) (27,36,45). Furthermore, all of the COFs family proteins are known to mainly function in the lipid transport to the organelle, and thus the characteristic binding mode might be suitable to perform this role.…”

“…Thus, both the PtdIns(4)P-specific site and the nonspecific basic groove are responsible for the Golgi localization of CERT. Structural Dynamics in the ␤1/␤2 Loops-The FAPP1 PH domain also recognizes PtdIns(4)P (36). A comparison of the tertiary structures between the CERT PH domain and the FAPP1 PH domain suggested that the dynamic nature of the ␤1/␤2 loop region could be different (supplemental Fig.…”

“…The FAPP1 and FAPP2 PH domains initiate membrane tubule formation in a PtdIns(4)P-dependent manner and are required for Golgi-to-plasma membrane vesicular transport (36 -39). The rigid ␤1/␤2 loop of the FAPP1 PH domain is considered to "wedge" into the Golgi and to reshape the lipid bilayer into a tubule form by increased membrane surface pressure (36). However, the CERT PH domain binding reportedly has no FIGURE 6.…”

“…In addition, most of the COFs family proteins are lipid transport proteins that are associated with the Golgi in a PtdIns(4)Pdependent manner (36,37,47). However, the proteins involved in signaling are usually specific to the di-or triphosphate forms of phosphoinositides (48 -51).…”