True Arrestins and Arrestin-Fold Proteins: A Structure-Based Appraisal - Progress in Molecular Biology and Translational Science - page 33

mammals and comprises five subunits divided into a trimeric cargo-selective
subcomplex (VPS35, VPS29, and VPS26) and a membrane-deforming sub-
complex (sorting nexins—SNXs harboring PX- and BAR domains).
4.1.1 Crystal structure of retromer subunits
The crystal structure of the retromer subunits has given clues to its functional
architecture.
VPS26 has a strong structural relationship to arrestins 11,12 with the char-
acteristic paired b -sandwich subdomains formed of antiparallel b -strands 48
( Fig. 2.3 ). The arrestin fold of crystallized VPS26A first appeared as
completely unexpected, as human VPS26 and arrestins share only about
10% identity and 20% overall homology.
VPS26 not only shares the arrestin fold but also the polar core and an
extended C-terminal tail. 11,12 There is, however, no evidence that the
mechanism of protein partner recognition functions in the same way, as
the salt bridge (Arg294-Glu117) at the subdomain interface of VPS26 is bur-
ied in the structure. A conformational change in this polar core would
require an extensive change in the interaction network at the interface,
and no signal or interactor to induce such a change has yet been found.
The current view of VPS26 structure proposes relative rigidity of the paired
subdomains with limited flexibility at their interface. 95
VPS26 binds VPS35, the cargo-recognition subunit of the retromer that
binds the cytosolic tail of the cargoes through their conserved sorting motif
[F,W]L[M,V]. 96 The VPS26 region interacting with VPS35 is an exposed
peripheral loop between strands b 15 and b 16 in the C-terminal subdomain,
far from the polar core. 11,95,97 VPS35 is predicted to be composed of 34
Figure 2.5 Modeled structure of Dictyostelium arrestin domain-containing protein
AdcA. The multistructure and ab initio model of Dictyostelium AdcA was calculated
on Phyre 2 web server in the intensive mode. It was modeled on 14 templates harboring
either an arrestin domain (bovine rod arrestin 1AYR and 1CF1, bovine b-arrestin-1 1G4M,
bovine b-arrestin-2 1JSY, Ambystona cone arrestin 1SUJ), or a FYVE domain (early
endosomal antigen 1 1JOC, hepatocyte growth factor-regulated tyrosine kinase sub-
strate 1DVP and 3ZYQ, endofin 1DVPA2 and 3T7L, Leishmania lm5-1 FYVE domain
1Z2Q), with a confidence value of 99-100%. The N-terminal region was modeled on
structures 1RW2, 3FW0, 1ZLG with a confidence of 58-61%. One hundred and thirty-
six residues were modeled ab initio and their structure is not reliable. The arrestin core
is colored in orange and extensions in olive green. Histidine residues of the N-terminal
His clusters (blue) and Zn-coordinating cysteines of the FYVE domain (purple) are shown
as sticks. A side view and a 90 tilted view are shown for a better appreciation of the
arrestin core and the histidine and cysteine clusters.