True Arrestins and Arrestin-Fold Proteins: A Structure-Based Appraisal - Progress in Molecular Biology and Translational Science - page 34

a -helices forming 17 HEAT-like repeats. 95,98 Such an a -solenoid arrange-
ment is found in other coat proteins (components of the AP adaptor com-
plex, clathrin) involved in trafficking. VPS35 binds also VPS29 via its
C-terminal ends and masks its metal-binding site. VPS29 harbors a fold strik-
ingly like that of Ser/Thr phosphatases. 99,100 Although the hypothesis of
VPS29 acting in control of the phosphorylated state of CI-MPR is very
appealing, it seems now established that VPS29 is not an active
metallophosphatase but serves as a scaffold for the binding of accessory pro-
teins. 101 VPS35 binds directly to the membrane-deforming SNXs. 93,102-104
The PX domains of SNX-BAR proteins are structured as a wedge with a
three-stranded b -sheet followed by a lipid-binding a -helical pocket accom-
modating phosphoinositides. The specificity of retromer-associated SNXs
for PI(3)P generally ascribed to the central positively charged amino acid
in the R[R,K]Y sequence 105 seems to hold for VPS5 and SNX1-2 but is
not obvious for VPS17, SNX5, and SNX6 where this position corresponds
to either S or Q. Their lipid specificity has been compiled elsewhere. 106
4.1.2 Regulation of the retromer ' s function
The list of retromer cargoes and functions has steadily grown. 97,107,108
Retromer functions now extend to polarized transport and apical-basal
polarity, cell surface recycling, transport frommitochondria to peroxisomes,
amyloid precursor protein sorting and processing, generation of morphogen
gradients, trafficking of pathogens, and many more. 107
Recruitment of the cargo-selective retromer complex to the endosomal
membrane is regulated by the small GTPase Rab7. 109 VPS29 110 and
VPS26 111 interact with a Rab GTPase-activating protein (GAP), TBC1D5.
The two retromer accessory proteins Rab7 and TBC1D5 represent thus a
molecular switch that catalyzes/downregulates the recruitment of the
VPS35-VPS29-VPS26 complex to the membrane. 112 The diversity of
the retromer cargoes and direction of trafficking are mediated by the use
of various SNXs and the recruitment of accessory proteins. A functional
analysis of VPS26A and VPS26B showed that they localize on early and late
endosomes, respectively, and that their differential cargo recognition is
linked to the variable C-terminal part of VPS26B. 111
Entamoeba histolytica is peculiar with five paralogues of VPS26 ( Fig. 2.2 )
and VPS35, but only one copy of VPS29. This situation is not unique, and
some Excavata ( Leishmania major , Naegleria gruberi , Trichomonas vaginalis ,
Giardia intestinalis , Trypanosoma brucei ) also harbor up to 6 VPS26 paralogues