The palm of the NTD contains
2 large interhelical loop insertions
stabilized by four disulfide
bonds. The CTD is also stabilized
by an extensive network of disulfide
subject to post-translational
Both modifications are necessary for
proper secretion, activity, and
engagement of the protein with the Fz
glycans are visible at
is especially important, as it forms the
basis for interaction with
Fz8 at binding site one.
Post-translational serine palmitoylation:
IV. Frizzled Receptor and
the Frizzled Cysteine Rich Domain
Frizzled receptors are 7-pass
transmembrane proteins containing
an extracellular cysteine-rich
domain (CRD) at the amino
terminus that binds Wnt proteins
with high affinity. The Fz8-CRD
possesses 10 conserved
within a domain of 120-125 amino acids. The CRD is
predominantly alpha helical, with all cysteines
The residues engaging in Wnt/Fz contact are
highly conserved in Wnt proteins,
however several contact residues found
in the Fz8-CRD are substituted in
other Frizzled-CRDs. For example,
, found in binding site 2, is conserved in 5 of 10
mammalian Fz-CRDs, but can be
substituted with valine, glutamic
acid, or aspartic acid in other
Frizzled receptors. This most likely
provides the specificity of Frizzled
receptors for subtypes of Wnt
V. Binding Site I
The palmitoleic acid lipid group
attached to the XWnt8 thumb directly
on Fz-CRD. This groove is lined with amino acids
that form extensive van der Waals
interactions with the lipid. In addition
to the hydrophobic effect, Wnt Lys182
with Fz8 Glu64 and a
with Fz8 Asn58.
Furthermore, thumb loop
form protein-protein contacts with the Frizzled CRD.
The primary driving force for the site 1
contact is the palmitoleic
interaction, while protein-protein
interactions involving residues at the
base of the thumb and slight shape
complementarity are secondary.
VI. Binding Site 2
The second Wnt/Fz binding site is located
opposite from site 1. It is composed of
between the Cys315-
bond at the tip of the XWnt8 index
finger, engaging in hydrophobic interactions
within a depression between
of the Fz8-CRD. The index finger reaching out to
site 2 is a long,
spanning from Arg301
to the C-terminal Cys321.
The finger positions
unusual tandem Cys320-Cys321
disulfide bond, and Val323
to form significant van der Waals
interactions with the apolar residues on the
CRD. The XWnt8 Trp319
sidechain at the tip of the finger sits in a
pocket of the CRD surface and
with Frizzled residues 150
to 152. Other
essential, conserved interactions occur
between Fz8 Tyr48
forming van der Waals
Overview of Wnt/Fz interactions:
Bazan, J., Janda, C., & Garcia, K. (2012). Structural Architecture and Functional Evolution of Wnts. Developmental Cell, 23(2), 227-232.
Huang, H., & Klein, P. S. (2004, June 14). The Frizzled family: Receptors for multiple signal transduction pathways. Genome Biology, 5(7), 234.1-234.7.
Christie, W. (. (n.d.). Proteolipids.
Retrieved December 10, 2016, from
Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C., & Garcia, K. C. (2012). Structural Basis of Wnt Recognition by Frizzled. Science, 337(6090), 59-64.
Komekado, H., Yamamoto, H., Chiba, T., & Kikuchi, A. (2007). Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a. Genes to Cells, 12(4), 521-534.
Kurayoshi, M., Yamamoto, H., Izumi, S., & Kikuchi, A. (2007). Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling. Biochemical Journal, 402(3), 515-523.
Nusse, R. (2005). Wnt signaling in disease and in development. Cell Research, 15(1), 28-32, 28-32.
Wnt signaling in C. elegans*. (n.d.). Retrieved December 15, 2016, from http://wormbook.org/chapters/www_wntsignaling.2/wntsignal.html
Christie, W. (. (n.d.). Proteolipids. Retrieved December 10, 2016, from http://www.lipidhome.co.uk/lipids/simple/protlip/index.htm
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