Three-dimensional Structural Interactions of Insulin and Its Receptor*,
Cecil C. Yip
and
Peter Ottensmeyer ¶
From the
Banting and Best Department of Medical
Research and the ¶Ontario Cancer Institute and
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G
2M9, Canada
Received for publication, May 22, 2003
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INTRODUCTION
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The insulin receptor
(IR)1 belongs to the
superfamily of transmembrane receptor tyrosine kinases (TKs) (reviewed in Ref.
1). In contrast to other family
members that are monomeric in their structure, IR and its homologue,
insulin-like growth factor I receptor (IGF-1R), are intrinsic disulfide-linked
dimers of heterodimeric disulfide-linked proteins of the form
(
)2. The 135-kDa
subunit of IR is
extracellular, whereas the 95-kDa
subunit contains an extracellular
portion, a single transmembrane sequence, and an intracellular TK domain.
Fig. 1a depicts the
major structural features of the 
dimer (see review by
Tavaré and Siddle (2)).
Ligand-specific binding to the
subunits activates the TK, initiating a
signal cascade that results in numerous cellular responses. Our understanding
of the mechanics of this signal transduction process has been hampered by the
unavailability of an atomic structure of the whole IR protein. However, the
quaternary structure of the isolated complex of biologically active IR and
insulin was recently solved by three-dimensional reconstruction from low dose
scanning transmission electron micrographs (STEM)
(3)
(Fig. 1, b1b3).
Atomic structures of subdomains of IR or of highly analogous proteins were
fitted into the complex (e.g. Fig.
1, b4), creating the only available atomic structural
model of IR. The model reveals structural details of the interaction of
insulin with the receptor that lead to the activation of the intracellular TK
(4). Here we review previous
biochemical observations on IR binding of natural and modified insulins and of
insulin-like growth factor 1 (IGF-1) against this atomic structural model, and
in the light of recent structural data on the unbound receptor, we discuss the
mechanics of a model of receptor activation arising from insulin binding.

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FIG. 1. Dimeric insulin receptor structure. a, schematic of IR
represented in its ( )2 form. Residues at the start of
named domains and disulfides (italics) are numbered. TM,
transmembrane; CT, C-terminal; juxtamembrane domains not labeled.
b, three-dimensional reconstruction from EM. b1, structure
at full volume of 480-kDa dimer (side view); b2, structure at 85% of
full volume to show domain subdivision (side view); b3, top view of
b2; regions 1, 2, and 3 represent epitope locations for
monoclonal Fab fragments 1844, 8314, and 8387
(37), respectively (see text
and Fig. 3e).
b4, ectodomain of EM structure (top view) fitted with atomic domains
LCL (green), Fn0 (blue), Fn1- ID
(red), Fn1-Fn2 (violet); backbone ribbon
representation. Second subunit is shown in brown. Arrow indicates
orientation of view of Fig.
2a. c, schematic of structural conformation in
b2. One monomer is labeled (color) and the second monomer is
white. In, insulin; A, activation loop and opposite
catalytic site; X, C terminus of subunit (white) and
N terminus of subunit (black); 1, 2, and 3,
disulfides at amino acids 524, 682685, and between 647 and 872,
respectively. Black bar represents 2-fold axis; solid and
open arrows point to insulin Phe-B25 and Glu-6 of
subunit.
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FIG. 3. IR signaling mechanics and conformational changes. a,
schematic closed IR form, insulin-bound, permissive for activation by
transphosphorylation. set 1 and set 2, amino acid
interactions with monomer 1 and monomer 2, respectively; C, catalytic
site; A-loop, activation loop; 1 and 2,
 disulfide bonds; cam, structural feature (bulge) on
CR. b, schematic open IR form, non-permissive for
transphosphorylation, cam blocks approach of A-loop to C site. c,
three-dimensional reconstruction of insulin-bound IR. d,
three-dimensional reconstruction of insulin-free IR. e, projection
images at different orientations of structures in c and d
showing Y, H, V, X, and parallel bar shapes like those seen in prior work
(4548).
Sixth column, modeled structures based on
Fig. 1, b4, of Fab/IR
images by Tulloch et al.
(37).
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FIG. 2. Accessibility of insulin Phe-B25. a, view of atomic insulin
receptor model in direction of arrows in
Fig. 1, b4; insulin
(purple) is between the L1CR domains of the two monomers
(green and brown). b, enlargement from a;
arrows are at Phe-B25 and N-terminal Glu-6 (start of IGF-1R
crystal structure (13); L1
(15)
not modeled). c, view perpendicular to b, showing accessible
locations of insulin Phe-B25 and L1 Glu-6.
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Three-dimensional STEM
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Although crystallography remains the technique of choice for atomic
structure determination of large proteins, considerable advances in electron
microscopy (EM) and in image processing have been made for three-dimensional
structure determination of proteins that are refractory to crystallization.
For a growing number of proteins, including the plant light-harvesting complex
(5), a human water channel
(6), and aquaporin-1
(7), three-dimensional
structural information has been obtained at resolutions of several Angstrom
units, revealing
-helices and other structural details.
In STEM, image acquisition is digital, as a 3-Å small electron beam
probe scans across the specimen at low temperature. Signal intensity is
directly proportional to the molecular mass of each molecule. Moreover, STEM
in dark field mode can readily visualize clusters of heavy atoms on
specifically marked biological molecules
(3,
8). STEM images have been used
to reconstruct three-dimensional structures of several proteins at resolutions
of 1220 Å, such as SRP54, the Klenow fragment of DNA polymerase
I, and IR (3,
912).
The STEM IR reconstruction at 20 Å was docked with atomic structures
of insulin and of subdomains of IR or highly similar proteins from
crystallography or NMR spectroscopy
(3,
4,
1317).
The resulting resolution is atomic within those domains and as accurate
between domains as the alignment of their centers of mass and their rotations.
For instance, the centers of mass of the 17.5 kDa L1 regions can be aligned in
their EM domains to within 3.0 Å, with larger domains located more
accurately. Rotational accuracy depends on recognizable asymmetries and is as
good as 5° for the L1-CR-L2 (LCL) region.
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Ligand-binding Tunnel in Insulin-IR Complex
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In the fitted structure of IR, the two atomic LCL regions formed a
diamond-shaped tunnel, the walls and the entrances of which were lined with
most of the amino acids known to be involved in insulin binding. One insulin
could be directly fitted into this tunnel as a rigid body to produce the side
chain pairings shown in Table
I. In this fit the insulin A chain interacts primarily
electrostatically with the L1 and L2 domains of one
subunit, with no
obvious hydrophobic components. The B chain interacts with the other
subunit, chiefly hydrophobically with L1 and electrostatically with CR. Thus
the model points to multisite interactions with IR, as expected from the
109 M1 binding affinity of
insulin.
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TABLE I Receptor-ligand side chain interactions Simultaneous close amino
acid pairings with observed side chain distances within 2.5 Å for
insulin or for IGF-1 in each of the modeled IR or IGF-1R ligand-binding
tunnels. Color scheme: dark yellow, hydrophobic; green,
polar; red, negative; blue, positive.
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The deduced interactions between insulin and LCL tunnel encompass insulin
residues A4, A5, B12, B16, B17, B24, and B26, out of 11 that are known to be
important in receptor binding
(1,
18,
19). These residues interact
to within 2.5 Å with residues 12, 34, 86, 89, 91, 247, and 249 among
those in the LCL region with known involvement in binding
(18,
2024).
Additional relevant receptor residues, such as 14, 250, and 323, are just
beyond this distance (4),
whereas 36, 39, and 64 (24)
not interacting directly with insulin in the model are on close facing regions
on the two L1 domains. Other important residues are discussed below.
Alanine scanning mutagenesis in the receptor
subunit segment
704716 outside of the LCL domain greatly decreases the receptor
affinity (25). In the
schematic placement of the receptor subdomains
(Fig. 1c), this
C-terminal sequence emerges from the
-
disulfide bond at
Cys-682, -683, or -685 (26) on
the 2-fold axis of the IR dimer. The
-terminal sequence 686719
can easily reach the insulin-binding tunnel. Residues within 704718
photocross-linked to carboxyamidated azido-Phe-B25 on insulin
(27), suggesting a
juxtaposition between this sequence and Phe-B25. Phe-B25, facing into the
entrance of the binding tunnel (Fig.
2), does not interact with the LCL regions in the atomic model
(4) but is important in
receptor binding. It is conceivable that it interacts hydrophobically with
Tyr-Leu (708709) as suggested by Kurose et al.
(27) or with Val-Val-Phe-Val
(712715). Tyr-Leu interaction with Phe-B25 would provide a structural
base for the suggestion (27)
that the C terminus (719) of the
subunit is near its N terminus
(Fig. 2). Deletion of insulin
C-terminal B26B30 did not decrease biological potency, implying that
this sequence of the B chain may affect the interaction of insulin with IR
through steric effects rather than binding
(28). Such a steric or
orientational role for this region is also suggested by the deduced
electrostatic interaction of insulin Lys-B29 with Asp-12 in L1
(4).
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Ligand Specificity and Ligand-binding Tunnel
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The primary amino acid sequence and the tertiary structure of all known
insulins are highly conserved (reviewed in Ref.
29). Nevertheless, several
insulins, including that of guinea pig, the Atlantic hagfish,
Amphiuma, chicken, and Xenopus, exhibit altered activity
from porcine, bovine, or human insulin when assayed using mammalian insulin
receptor. The altered bioactivities of guinea pig and Amphiuma
insulins were readily explained by the structural fitting of insulin in the
binding tunnel (4). For chicken
and Xenopus insulins
(30,
31) the 23-fold greater
activity was attributed to a common Thr-A8 to His substitution along with
Ser-A9 to Asn in chicken insulin. As also modeled for Amphiuma, the
replacement His residue can reach Asp-59 in the L1 domain to potentiate
binding. Moreover, Asn-A9 in chicken insulin can readily bond with Gln-328 of
IR.
The binding affinity of hagfish ligand is about 25% of that of porcine
insulin, and its biological potency is less than 5%
(32). Significant sequence
changes are Phe-B1 to Arg, Ser-B9 to Lys, Thr-A8 to His, Ser-A9 to Lys, and
Ile-A10 to Arg. When hagfish insulin is fitted into the mammalian LCL tunnel,
His-A8 can bond with Asp-59 and Arg-A10 with Glu-329. However, Arg-B1 is
positioned to repel Lys-B29 and compete for its interaction with Asp-12,
disrupting the proposed orientational function
(28) and permitting Lys-B9 to
bond Asp-12 (on monomer B). A resulting misalignment of hagfish insulin
between the two human LCLs could create the observed consequences on
biological signaling.
The biological activity of insulin analogues with specific amino acid
substitutions has been extensively studied. A His-B10 to Asp change resulted
in a superactive insulin (21),
explainable by a stronger ionic interaction with Arg-14 in the binding tunnel.
On the other hand, the interchange of Pro-B28 and Lys-B29 in the Lys-Pro
insulin produces no major alterations in binding
(33). In the model, lysine in
either position can bond with Asp-12 on L1.
The invariant B23-B26 core (Gly-Phe-Phe-Tyr) has been probed by replacement
of the aromatic residues with less hydrophobic amino acids. For both
[Leu-B24]- and [Leu-B25]insulins, receptor binding activity and biological
activity were 10 and 1%, respectively, of porcine insulin
(34). [Leu-B24]Insulin, but
not [Leu-B25]insulin, was a partial antagonist. In the model Phe-B24 lies flat
in the surface of insulin while interacting with the side chain of Leu-87 of
L1. A bulkier and longer Leu-B24 side chain would cause a slight separation
between facing hydrophobic surfaces on insulin and L1 to account for lower
binding and could correspondingly separate and misalign the two LCLs just
enough to lessen biological potency. Thus [Leu-B24]insulin could act as a
partial antagonist.
The role of Phe-B25 is more complex. Not only is Phe-B25 important for
insulin binding, it also enhances the release of receptor-bound insulin, a
kinetic phenomenon described as negative cooperativity
(35,
36). Previous studies
(27,
28,
34) placed Phe-B25 near the
704719 tail of the IR
subunit. The accessible position of
Phe-B25 in the IR model (Fig.
2) easily permits this. Low affinity insulin analogues, in which
Phe-B25 was replaced by Ala, Ser, Leu, or homophenylalanine
(28), abrogated negative
cooperativity, possibly because of a reduced interaction with the
tail. However, a truncated carboxyamidated [Phe-B25]des(B2630)insulin
bound better than native insulin and retained negative cooperativity. Its
azido derivative cross-linked to the
tail, suggesting that the
non-azido form could also bind this region. Similarly, such truncated insulins
with Leu-B25, Ser-B25, Ala-B25, or homo-Phe-B25 all retained 50% or more
negative cooperativity compared with native insulin
(28), suggesting that the
binding of B25 to the
tail of IR still occurred through the
carboxyamide moiety. This should be testable. Thus negative cooperativity,
which demands multiple sites of ligand-receptor interactions
(35,
36), may for IR require also
specific binding to the
subunit C-terminal sequence.
Like Phe-B25, Tyr-A19 is important for receptor binding and biological
potency (38), yet it does not
interact with LCL in the atomic model. Structurally it is sandwiched between
Asn-A18 and Ile-A2 and interacts edge-on with the plane of the phenyl ring of
Phe-B25. Modifications or substitutions of Tyr-A19 can therefore directly
affect the functional role of Phe-B25.
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IGF-1, IR, and IGF-1R
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IGF-1 and insulin are homologous peptide hormones that bind to homologous
but different receptors. IGF-1 is a single-chain polypeptide with four
sequential structural domains, B, C, A, and D. The B and A domains are
equivalent to the B and A chains of insulin, and their secondary structure can
be largely superposed (39).
The D domain extends 8 residues beyond the A chain. The C domain is equivalent
to the C peptide of proinsulin. Despite these strong similarities, insulin and
IGF-1 bind only weakly to the alternative receptor. Extensive investigations
indicate that this binding specificity for IR and IGF-1R resides in different
regions of a common binding site
(40,
41).
These findings are corroborated by an examination of the atomic model in
which insulin is replaced by IGF-1
(13) (Protein Data Bank
accession number 2GF1
[PDB]
), and the positions of the LCL regions in IR are
substituted by the exact crystal structure of the LCL domains of IGF-1R
(42) (Protein Data Bank
accession number 1IGR
[PDB]
). The pairwise amino acid interactions found are shown
in Table I. For insulin on IR,
14 close interactions were obtained. For IGF-1 on IR, the ligand had to be
rotated to relieve a serious steric hindrance between the D-domain of IGF-1
and the L2 region of IR. Then only 11 pairwise interactions formed.
Conversely, for IGF-1 on IGF-1R 14 pairs of interactions were obtained,
whereas insulin in the IGF-1R tunnel had only 10 close interactions. The
character of binding (hydrophobic, polar, etc.) also changed. Nevertheless,
the atomic models based on the IR configuration indicate that the 10-fold
weaker binding of each hormone to the homologous receptor is accompanied by a
reduction of side chain interactions.
The pattern of interaction of each hormone with its homologous receptor is
also different (Table I).
Insulin binds predominantly to the L1 regions on IR, whereas IGF-1 has a
preference for the CR regions and L2 on IGF-1R. Both hormones virtually eschew
the CR regions of the homologous receptors, equally preferring the L1 and L2
domains. It is known that the CR region confers binding specificity in IGF-1R
and that L1 and L2 do so in IR
(13,
18,
40,
41).
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The Mechanics of Transmembrane Signaling
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A fundamental question on the mechanism of transmembrane activation of
receptors by extracellular ligand binding is how the binding action is
transformed into key intracellular biochemical reactions such as receptor
autophosphorylation. Inactive monomeric TK receptors, such as the epidermal
growth factor receptor and platelet-derived growth factor receptor, are
dimerized and activated by ligand binding (see Ref.
43 for review). Because IR is
intrinsically dimeric without insulin, the distance between the cytoplasmic
TKs must be too large for activation without ligand binding. In the
three-dimensional reconstruction of the insulin-bound IR complex the two TK
domains are juxtaposed, and an extended flexible activation loop of one fitted
atomic TK structure can just reach the catalytic loop of the other TK
(3). In a simple mechanical
paradigm of activation (4) the
binding of insulin not only overcomes an energy barrier to binding but holds
the LCL domains together to permit a lateral shift and approach of the two
transmembrane domains to allow trans-autophosphorylation of the
tyrosine residues in the activation loop
(4)
(Fig. 3, a and
b).
The model presupposed an "open" configuration of the free IR.
Such a configuration has been confirmed by the three-dimensional
reconstruction from STEM micrographs of insulin-free IR dimers
(44)
(Fig. 3d). Moreover,
this structure, together with the insulin-bound three-dimensional structure,
makes it possible to reconcile virtually all structural forms seen previously
in electron microscopic examinations of the IR, except for long parallel
T-shaped structures occasionally observed
(45,
46). This includes Y, H, V,
and X shapes and parallel barlike images, observed by two-dimensional electron
microscopy of detergent-solubilized IR, its ectodomain, or
vesicle-reconstituted insulin-IR complex
(4548).
Such configurations can be formed by the projection of the three-dimensional
reconstructions at various orientations
(Fig. 3e). Moreover,
the three-dimensional reconstruction can also explain the images of parallel
rods and crosses (Fig.
3e, last column) produced by pairs of antibodies
to Fn0, to the
-ID, and to the CR domain
(37).
 |
Summary
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Electron microscopic imaging of the large insulin receptor protein in
complex with insulin and in its free form, coupled with three-dimensional
reconstruction and fitting of atomic subdomains, has yielded a structural
model that permits an understanding of insulin binding at the atomic level.
The model corroborates and explains the biological activity and binding
behavior of virtually all naturally occurring insulins and insulin analogues,
as well as the effects of receptor mutations on insulin binding. The model
also provides a basis to address the fundamental question on the mechanism of
transmembrane activation of receptors by ligand binding.
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FOOTNOTES
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* This minireview will be reprinted in the 2003 Minireview Compendium, which
will be available in January, 2004. 
The on-line version of this article (available at
http://www.jbc.org)
contains movie files showing domain docking. 
To whom correspondence should be addressed: Banting and Best Dept. of Medical
Research, University of Toronto, 112 College St., Toronto, Ontario M5G 1L6,
Canada. Tel.: 416-946-7006; Fax: 416-946-8253; E-mail:
cecil.yip{at}utoronto.ca.
1 The abbreviations used are: IR, insulin receptor; TK, tyrosine kinase;
IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1
receptor; EM, electron microscopy; L1 and L2, large domain 1 and 2; CR,
Cys-rich region; LCL, L1-CR-L2; STEM, scanning transmission electron
micrograph; Fn, fibronectin III-like; ID, insert domain. 
 |
ACKNOWLEDGMENTS
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We thank Puja Malik, Daniel Beniac, and Allan Fernandes, for insights,
cross-checks, and creative and artistic technical assistance, and Ira Goldfine
for stimulating discussions on IR and IGF-1R.
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