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From the
Received for publication, July 21, 2000
Subtypes of the calcium-independent
receptors for Most neuronal cell surface receptors are attached to intracellular
proteins via specific protein/protein interactions; this has been
demonstrated in a number of cases involving ligand gated ion channels
and G-protein-coupled receptors, as well as cell adhesion molecules
(e.g. Refs. 1-3). A protein module frequently involved in
this type of interaction is the
PDZ1 domain, which can
specifically contact the intracellular C terminus of distinct membrane
proteins (e.g. Ref. 1). It is generally believed that this
type of interaction serves a function in anchoring receptors to the
cytoskeleton, thus leading to the targeting of receptors to their
presumed site of action, e.g. in the postsynaptic specializations of neurons. In addition, the interaction with PDZ
domains may be important for the recruitment of receptors to specific
signal transduction pathways, as exemplified by the interaction of
Recently, a novel group of cell surface receptors has been described
that resembles the G-protein-coupled receptor superfamily because it
shares the typical pattern of seven hydrophobic transmembrane regions.
A characteristic feature of this new family is the very large
N-terminal, extracellular part, which may contain several domains
usually found in cell adhesion molecules. A prototype of this group of
receptors is the calcium-independent receptor for Here, we show that the intracellular C terminus of CIRLs binds with
high affinity to the PDZ domains of the
ProSAP/SSTRIP/Shank2 family
of multidomain proteins. Recently, it has been shown by several groups
that ProSAP/SSTRIP/Shank proteins are important structural constituents
of synaptic structures in human and rodent brain (4-8, 10).
ProSAP/SSTRIP/Shank have been shown to interact with the C terminus of
the somatostatin receptor subtype-2 (3, 4) and with members of a PSD
protein family termed SAPAP/GKAP (SAP90/PSD95-associated
protein/guanylate kinase-associated protein) (5, 6, 8, 10). The latter
interact directly with postsynaptic scaffold proteins (20-25). The
data reported here suggest that members of the ProSAP/SSTRIP/Shank
protein family are also involved in the synaptic targeting of CIRLs and
thus may contribute to signal transduction events mediated by the so
far unknown physiological ligands of these receptors.
Materials--
Rabbit antisera against the N-terminal regions of
CIRL1 and CIRL2 were generously supplied by Drs V. Krasnoperov and A. Petrenko (New York University School of Medicine, New York). The
antiserum directed against the C terminus of ProSAP1 was described
previously (7).
Yeast Two-hybrid Screening--
The PDZ domain of human SSTRIP
cloned into pAS1-Cyh2 (CLONTECH Laboratories Inc.,
Palo Alto, CA) and the PDZ domain of rat ProSAP1 cloned into pAS2 were
used as bait for screening human and rat brain Matchmaker two-hybrid
cDNA libraries (CLONTECH), respectively, as
described (3, 7, 8).
In Situ Hybridization--
Rat brains were cut with a cryostat
in horizontal sections (18 µm), CIRL mRNAs were detected with
cDNA antisense oligonucleotides purchased from MWG-Biotech
(Ebersberg, Germany): CIRL1 (GenBankTM accession no.
U72487), 5'-TCC-AGA-GTG-CTG-CAG-CCA-AGC-GGG-CCA-TGG-CGA-A-3' (bp
112-78); CIRL2 (GenBankTM accession no. AF 063102),
5'-GGC-TGC-TCT-GCT-GAA-ACC-TTC-GGT-ATT-CGG-TGA-G-3' (bp 113-79) and
5'-TCA-GGA-CTG-TGC-ACG-GGT-GTG-GGG-GAC-CGG-GAA-3' (bp 3644-3612); and
CIRL3 (GenBankTM accession no. AF063103),
5'-AGG-GCC-TCC-TGG-GCT-GTG-CTC-AGC-ATG-TCG-CAG-3' (bp 230-197).
Hybridization was performed as described previously (7).
Fractionation of Rat Brain Membranes--
Crude synaptosomal and
PSD fractions were prepared from adult rat brain as described (26). The
PSD/One Triton fraction was used for Western blotting
experiments as previously described (4).
Immunoprecipitation from Rat Brain Membranes--
ProSAP1
antiserum (5 µl) was coupled to NHS-activated Sepharose
(Amersham Pharmacia Biotech) following the manufacturer's instructions. Crude membranes derived from rat brain (2 mg total protein) were solubilized in RIPA buffer (0.1% SDS, 0.5% sodium deoxycholate, 1% Nonidet P-40, 50 mM Tris-HCl, pH 8.0, 150 mM NaCl) at 37 °C for 30 min followed by incubation on
ice for 30 min. Insoluble matter was removed by centrifugation at
20,800 × g for 30 min, and the supernatant fractions
were incubated with the immobilized antiserum overnight at
4 °C. After washing extensively in RIPA buffer, the precipitates
were eluted with Laemmli sample buffer containing 8 M urea,
separated on 8% polyacrylamide gels containing 8 M urea,
and electroblotted onto nitrocellulose. CIRL proteins were detected
using CIRL1- and CIRL2-specific antisera followed by alkaline
phosphatase detection.
Interaction between the PDZ Domain of Human SSTRIP/Rat ProSAP1 and
the C Terminus of CIRLs--
To identify potential candidates
interacting with members of the SSTRIP/ProSAP family, the PDZ domain of
human SSTRIP was used as bait in the yeast two-hybrid system. By
screening a human brain cDNA library, we observed a specific
interaction with a clone containing the C-terminal part of
latrophilin-2, the human homologue of CIRL2 (27) and four clones
containing the C-terminal part of brain angiogenesis inhibitor-2
(BAI-2; Ref. 19). In an independent yeast two-hybrid experiment,
the highly homologous PDZ domain of ProSAP1 was used to screen a rat
brain cDNA library. In this case, four independent, specifically
interacting clones all coding for the C terminus of the rat CIRL1
protein were obtained (Table I). Both the
CIRL and the BAI proteins have recently been identified as
seven-transmembrane proteins, characterized by an exceptionally large
extracellular domain. The C-terminal sequences of CIRL1 and CIRL2 are
very similar to each other and contain typical consensus sequences for
the interaction with PDZ domains, i.e. the sequence motif
S/T-X-
The CIRL-SSTRIP/ProSAP interactions detected by the yeast two-hybrid
system were further verified by overlay assays using GST fusion
proteins of the PDZ domains of rat ProSAP1 and human SSTRIP. The
biotinylated fusion proteins of the C termini of the CIRL and BAI
proteins were used as probes (3). As depicted in Fig.
1, the overlay assays revealed strong
interactions of the PDZ domain of rat ProSAP1 with both CIRLs but not
with BAI-2. Using the PDZ domain of human SSTRIP, an interaction with
the C terminus of CIRL1, but neither CIRL2 nor BAI-2, was observed, suggesting that the interaction of the PDZ domain of ProSAP1 and the C
termini of CIRL1 and -2 exhibits a higher affinity than that between
SSTRIP and the two CIRLs. Interactions of ProSAP1 and SSTRIP with BAI-2
were sufficient in the yeast two-hybrid system but were absent in the
overlay assay, indicating that they may be of little physiological
significance. Therefore, we have focused our further studies on the
interaction of SSTRIP/ProSAP1 with the
To verify our findings in vivo, we performed
co-immunoprecipitation experiments using plasma membrane fractions of
rat brain and specific antibodies raised against the two proteins.
Initial attempts with membrane fractions solubilized by boiling in
Laemmli buffer did not yield CIRL1 or CIRL2 immunoreactivity (CIRL
antibodies were directed against the N-terminal extracellular regions)
in Western blotting experiments. Significant bands at the anticipated molecular weight of 120 kDa for CIRL1 and at ~140 kDa for CIRL2 were
detected only when solubilization of the membranes was performed in the
presence of 8 M urea at 37 °C (Fig.
2A). As ProSAPs are not easily
soluble in nondenaturing detergents (7, 8), as well as to compromise
between the different solubility characteristics of ProSAPs and CIRLs,
the brain membrane fractions were treated with RIPA buffer containing
0.1% SDS at 37 °C. Under these conditions, ProSAP1 was efficiently
immunoprecipitated from solubilized rat brain membranes using an
antibody directed against the C terminus. In this reaction, CIRL1 but
not CIRL2 was coprecipitated (Fig. 2B). Thus, although
in vitro both the C termini of CIRL1 and CIRL2 interact with
the PDZ domain of ProSAP1, in vivo a physiological protein/protein interaction appears to occur only between CIRL1 and ProSAP1.
Coexpression of ProSAP1 and CIRL1--
As CIRLs are involved in
the presynaptic action of
As no data on the temporal and regional patterns of expression of the
CIRL proteins in brain were available, we compared the distribution of
mRNAs coding for ProSAP1 and CIRL1-3 by in situ hybridization experiments using specific oligonucleotide probes on rat
brain sections (Fig. 3A). In
agreement with previous observations, ProSAP1 is expressed very early,
during postnatal development, and is widely distributed in the central
nervous system of rats. Particularly high levels are detected in the
cortex, the hippocampus (CA1-CA3 regions and the dentate gyrus), and
the Purkinje cell layer of the cerebellum. CIRL1 mRNA is present
during early development. However, the highest expression levels are
detected at the age of 2-3 weeks, with a moderate decline toward
adulthood. CIRL1 was found mainly in the cortex, the CA1-CA3 regions
of the hippocampus, the dentate gyrus, and in the cerebellum in a
pattern largely overlapping that of ProSAP1. Lower levels of expression
were detected also in the caudate putamen. In contrast to CIRL1,
expression levels of CIRL2 peaked during early postnatal development
and declined during adult life, with an almost complete loss of
expression in the 1-year-old rat. The regional distribution of CIRL2
was also strikingly different when compared with CIRL1. In particular, expression is strong in the CA1 region of the hippocampus but is absent
in CA2 and CA3 as well as in the dentate gyrus. Strong labeling was
also observed in the thalamus and in caudate putamen. CIRL3 exhibited
its highest expression level immediately after birth, thus preceding
both CIRL1 and CIRL2. Whereas expression in the forebrain is strongly
reduced in the adult stages, expression of CIRL3 is maintained in the
cerebellum of adult rats. When comparing the expression profiles of
ProSAP1 and CIRL1, both are largely identical, again supporting the
notion that CIRL1 and ProSAP1 are physiologically interacting
partners (Fig. 3B).
The data shown here provide evidence for a novel interaction
between the PDZ domain of ProSAP/SSTRIP/Shank proteins and the seven
transmembrane-spanning, putative G-protein-coupled receptors for
An important question remains as to the actual location in neurons
where CIRL1 and ProSAP1 interact. Because of the toxic principle of
Taken together, the presence of CIRL on pre- and postsynaptic elements
of synapses, the highly regulated pattern of CIRL isoform expression,
and the domain structure of its extracellular region suggest a role for
CIRL proteins as cell adhesion molecules during synaptogenesis, which
may be mediated in part through interactions of the C terminus with
synaptic scaffolding molecules of the ProSAP/SSTRIP/Shank multidomain
protein family.
We thank Hans-Hinrich Hönck,
Gisela Gaede, and Annelie Ahle for excellent technical assistance and
Drs. Alexander Petrenko and Valery Krasnoperov (Department of
Pharmacology, New York University School of Medicine, New York) for
CIRL antibodies.
*
This work was supported by Deutsche Forschungsgemeinschaft
SFB545/B7 (to H.-J. K. and D. R.) and SFB426/A1 (to E. D. G.), the
European Commission (QLG3-CT-1999-00908 to D. R.), and
Universität Münster (IMF and IZKF/F1, to T. M. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
§
Presented this work as part of a thesis requirement.
Published, JBC Papers in Press, August 29, 2000, DOI 10.1074/jbc.C000490200
2
Because of the fact that the ProSAP/SSTRIP/Shank
protein family has been discovered independently by several groups, the
terminology for the three members existing thus far varies as follows:
SSTRIP/Shank1/Synamon (4-6), ProSAP1/CortBP1/Shank2 (5, 7-9), and
ProSAP2/Shank3 (7, 8, 10).
3
T. M. Böckers, data not shown.
The abbreviations used are:
PDZ, PSD-95/discs
large/ZO-1;
BAI, brain angiogenesis inhibitor;
CIRL, calcium-independent receptors for
ACCELERATED PUBLICATION
The Calcium-independent Receptor for 
-Latrotoxin from Human
and Rodent Brains Interacts with Members of the ProSAP/SSTRIP/Shank
Family of Multidomain Proteins*
,§,
, and Institut für Zellbiochemie und
Klinische Neurobiologie, Universität Hamburg,
Martinistrasse 52, 20246 Hamburg, ¶ Leibnitz Institut für
Neurobiologie, Brenneckestrasse 6, 39118 Magdeburg, and ** Institut
für Anatomie, Westfälische Wilhelms-Universität
Münster, Vesaliusweg 2-4, 48149 Münster, Germany
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
latrotoxin (CIRL1-3) define a distinct subgroup
within the large family of the seven-transmembrane region cell surface
receptors. The physiological function of CIRLs is unknown because
neither extracellular ligands nor intracellular coupling proteins
(G-proteins) have been identified. Using yeast two-hybrid screening, we
identified a novel interaction between the C termini of CIRL1 and -2 and the PSD-95/discs
large/ZO-1 (PDZ) domain of a recently discovered multidomain protein family (ProSAP/SSTRIP/Shank) present in human and
rat brain. In vitro, CIRL1 and CIRL2 interacted strongly
with the PDZ domain of ProSAP1. The specificity of this interaction has
been verified by in vivo experiments using solubilized rat brain membrane fractions and ProSAP1 antibodies; only CIRL1, but not
CIRL2, was co-immunoprecipitated with ProSAP1. In situ
hybridization revealed that ProSAP1 and CIRL1 are co-expressed in the
cortex, hippocampus, and cerebellum. Colocalization was also observed at the subcellular level, as both CIRL1 and ProSAP1 are enriched in the
postsynaptic density fraction from rat brain. Expression of all three
CIRL isoforms is highly regulated during postnatal brain development,
with CIRL3 exhibiting its highest expression levels immediately after
birth, followed by CIRL2 and finally CIRL1 in aged rats.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-adrenergic receptors with the
Na+-/H+-exchanger regulatory protein (11).
-latrotoxin
(CIRL). Together with neurexin 1a, CIRL is present on axon terminals,
where it is thought to tether the toxin from black widow spider venom
to presynaptic structures; this facilitates insertion of -latrotoxin
into the plasma membrane which then leads to massive exocytosis of
neurotransmitter (12, 13). Three isoforms of CIRL have been identified
by molecular cloning (latrophilin 1-3/CIRL1-3 (14-16)). CIRLs have
been shown to contain two subunits, derived from a common precursor by
proteolytic processing and linked together by disulfide bonds (17, 18).
Together with the brain angiogenesis inhibitor proteins (19), the Emr1 protein, CD97, and the HE-6 protein, about 15 members of this receptor family can be identified by data base searches (see Ref. 14).
However, the physiological function of CIRLs remains enigmatic, particularly because neither the physiological ligands nor
intracellular signal transducing proteins are known. To shed more light
on the function of CIRLs, it will be necessary to determine their
cellular and subcellular distribution. In addition, the identification of intracellularly associated proteins may help to delineate the signal
transduction pathway in which CIRLs are involved.
EXPERIMENTAL PROCEDURES
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
; where is a large, hydrophobic amino
acid residue. This motif is also shared by BAI-2, suggesting that all
three receptors identified here (i.e. CIRL1, CIRL2, and BAI-2) are potential interaction partners for the PDZ domains of the
SSTRIP/ProSAP protein family.
C-terminal sequences of targets obtained from yeast two-hybrid screens
with SSTRIP/ProSAP PDZ domains compared to several known targets
-latrotoxin receptor
isoforms.
View larger version (16K):
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Fig. 1.
In vitro protein interactions of
the PDZ domains of SSTRIP and ProSAP1. GST fusion proteins
containing the PDZ domains of human SSTRIP or rat ProSAP1 and as a
control GST alone were run on polyacrylamide gels and stained with
Coomassie Brilliant Blue (left panel) or blotted onto
nitrocellulose membranes and processed for overlay assay; membranes
were probed with the biotinylated fusion proteins containing the C
termini of CIRL1, CIRL2, and BAI-2 (Bai2) as indicated.
Specifically, bound fusion proteins were detected with alkaline
phosphatase coupled to avidin.
View larger version (24K):
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Fig. 2.
Interaction of CIRL1 and ProSAP1 in
vivo. A, solubility characteristics of CIRL
proteins. Rat brain membranes were solubilized in Laemmli sample buffer
in the absence or presence of 8 M urea. After separation on
8% polyacrylamide gels and blotting onto nitrocellulose, CIRLs were
detected using specific rabbit antisera as indicated. Alkaline
phosphatase coupled to goat anti-rabbit was used as the secondary
antibody. IB, immunoblot. B, immunoprecipitation
from solubilized rat brain membranes. Rat brain membranes were
solubilized, and ProSAP1 was precipitated using the rabbit ProSAP1
antiserum. Samples of lysates (lys), supernatants
(sup), and precipitates (prec) were processed for
Western blotting as described in A, including 8 M urea in sample buffer and gel matrix. The molecular
weight shown here for CIRL2 is slightly higher than predicted. However,
we also observed that the ProSAP1-specific bands shifted to higher
molecular weights when gels were run in 8 M urea (data not
shown). CIRL1 and CIRL2 antibodies were used for the detection of
blotted proteins. The strong band at 75-100 kDa in immunoprecipitates
(IP) is due to rabbit antibody leaking from the column,
which is detected strongly in the Western blotting experiments by the
anti-rabbit alkaline phosphatase conjugate. The position of CIRL1 in
the precipitate is indicated by an arrow. C, enrichment of
CIRL1 in postsynaptic densities. 40 µg of each crude (c),
synaptosomal (s), and postsynaptic (p) density
fractions were analyzed by Western blotting using CIRL1- and
CIRL2-specific antibodies.
-latrotoxin, whereas the
ProSAP/SSTRIP/Shank proteins are constituents of postsynaptic
structures (4, 5, 7, 8), we investigated whether CIRLs might also be
present in postsynaptic membrane fractions. By Western blotting, we
detected enrichment of the CIRL1 protein in the PSD fraction from rat
brain confirming that the specific interaction between ProSAP1 and
CIRL1 correlates with the presence of both proteins in the PSD. In
contrast, CIRL2 was present only in crude and synaptosomal fractions
but not in the PSD fraction (Fig. 2C).
View larger version (76K):
[in a new window]
Fig. 3.
Postnatal expression patterns of ProSAP1 and
CIRL isoforms in rat brain. A, overview. The regional
distribution of ProSAP1 (top) and CIRL1-3 transcripts in
various developmental stages of the rat brain was determined by
in situ hybridization. Shown are horizontal sections taken
from the brains of (from left to right) 1-, 3-, 8-, and 16-day-, 3-week-, 3-month-, and 12-month-old rats.
Cx, cortex; CA1-3, Cornu ammonis regions of the
hippocampus; Cb, cerebellum; Th, thalamus;
CPu, caudate putamen. B, enlargement of the
hippocampal regions. Horizontal sections were taken from 3-week-old
rats.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-latrotoxin, CIRL1. The interaction is presumably driven by the very
C terminus of the CIRL protein, which carries a typical recognition
motif for the PDZ domain. Data previously obtained with the PDZ domains
of ProSAP/SSTRIP/Shank (4, 5) and those presented here may help to
delineate the structural constraints that determine the specificity in
the interaction of ProSAP/SSTRIP/Shank with proteins carrying the PDZ
recognition motif. Thus, a larger hydrophobic residue (isoleucine or
leucine) in the last position of the consensus sequence is required for
binding (see Fig. 1), whereas valine (which is required for the NMDA
(N-methyl-D-aspartate) receptor/PSD-95/SAP102 interactions (1) is not present in this position in any of the interacting proteins. In agreement with the data
obtained by Naisbitt et al. (5), a negative charge is not
tolerated in the 2 position, as seen here for BAI-2, which interacts only with low affinity (see Table I and Fig. 1). On the other
hand, specificity may not exclusively be determined by the PDZ
recognition motif; CIRL1-3 carry identical PDZ consensus sequences at
their C termini (last five amino acid residues), and yet only CIRL1 has
been found to interact specifically in vitro and in
vivo with ProSAP1.
-latrotoxin, which induces neurotransmitter release after binding to
CIRL and neurexin (12), CIRL has been assumed to be a presynaptic
receptor. ProSAP1 and other members of this protein family, however,
have been shown to be highly enriched in the postsynaptic density of
neurons (4, 5, 7, 8). The CIRL antibodies available to us were not
suitable for ultrastructural analysis,3 which could
ultimately solve this question. We show here the presence of CIRL1 in
the postsynaptic membrane fraction derived from rat brain.
Additionally, it appears possible that isoforms of the
ProSAP/SSTRIP/Shank family are also present in presynaptic compartments
of neurons. Because of the unique extracellular domain structure of
CIRL, which includes several motifs otherwise found in cell adhesion
molecules, it has been suggested that CIRLs and related receptors
function as such and not as G-protein-coupled receptors that bind to
soluble, secreted ligands. In this respect, our data indicate that
CIRLs are involved in neuronal cell adhesion events, possibly during
synaptogenesis, by acting on presynaptic, axonal elements as well as
the postsynaptic, dendritic structures. In agreement with a role in
synaptogenesis, CIRL expression is highly regulated during development.
CIRL3 expression peaks very early in development, with the highest
levels observed immediately after birth. CIRL2 mRNA is also present
during early postnatal development, reaching its peak expression level
a few days later. During later stages, the roles of CIRL2 and -3 may be
taken over by CIRL1, which shows an increase in expression concomitant
with the loss of CIRL3 and especially CIRL2, which is hardly detectable in the aged rat. CIRL3 expression remains strong in the cerebellum, where it partially matches that of ProSAP1. It appears possible that an
interaction occurs between these two proteins in the cerebellum, as the
C-terminal sequence of CIRL3 (-HLVTSL-Stop) is similar to that of the
other CIRLs. However, as no CIRL3 clone was detected in our yeast
two-hybrid screen, and because no CIRL3 specific antibodies were
available to us, we were unable to verify this possibility.
ACKNOWLEDGEMENTS
FOOTNOTES
To whom correspondence should be addressed: Institut für
Zellbiochemie und klinische Neurobiologie, Universität Hamburg, Martinistrasse 52, 20246 Hamburg, Germany. Tel.: 49-40-42803-3344; Fax:
49-40-42803-2345; E-mail: richter@uke.uni-hamburg.de.
ABBREVIATIONS
-latrotoxin;
CA1-3, Cornu ammonis
regions 1-3;
GST, glutathione S-transferase;
ProSAP, proline-rich synapse-associated protein;
PSD, postsynaptic density;
RIPA, radioimmune precipitation;
SAP, synapse-associated protein;
SSTR, somatostatin receptor;
SSTRIP, SSTR-interacting protein;
bp, base pair(s).
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