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§1§ The crystal structure of a multifunctional protein: Phosphoglucose
isomerase/autocrine motility factor/neuroleukin §1§
1. [16]Yuh-Ju Sun [17]*,
2. [18]Chia-Cheng Chou [19]* , [20],
3. [21]Wei-Shone Chen [22],
4. [23]Rong-Tsun Wu [24]§,
5. [25]Menghsiao Meng [26]¶, and
6. [27]Chwan-Deng Hsiao [28]* , [29]‖
1.
^*Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
11529, Republic of China; ^Graduate Institute of Life Science,
National Defense Medical Center, Taipei, Taiwan 11217, Republic of
China; ^Veterans General Hospital, Taipei, Taiwan 11221, Republic of
China; ^§Graduate Institute of Biopharmaceutical Science, National
Yang-Ming University, Taipei, Taiwan 11221, Republic of China; and
^¶Graduate Institute of Agricultural Biotechnology, National Chung
Hsing University, Taichung, Taiwan 40227, Republic of China
1. Edited by Robert Huber, Max Planck Institute for Biochemistry,
Martinsried, Germany, and approved March 20, 1999 (received for
review December 21, 1998)
[30]Next Section
§2§ Abstract §2§
Phosphoglucose isomerase (PGI) plays a central role in both the
glycolysis and the gluconeogenesis pathways. We present here the
complete crystal structure of PGI from Bacillus stearothermophilus at
2.3-Å resolution. We show that PGI has cell-motility-stimulating
activity on mouse colon cancer cells similar to that of endogenous
autocrine motility factor (AMF). PGI can also enhance neurite outgrowth
on neuronal progenitor cells similar to that observed for neuroleukin.
The results confirm that PGI is neuroleukin and AMF. PGI has an open
twisted α/β structural motif consisting of two globular domains and two
protruding parts. Based on this substrate-free structure, together with
the previously published biological, biochemical, and modeling results,
we postulate a possible substrate-binding site that is located within
the domains interface for PGI and AMF. In addition, the structure
provides evidence suggesting that the top part of the large domain
together with one of the protruding loops might participate in inducing
the neurotrophic activity.
Phosphoglucose isomerase (PGI; EC [31]5.3.1.9) is a glycolytic enzyme
that catalyzes the reversible isomerization of glucose-6-phosphate to
fructose-6-phosphate. PGI deficiency in humans leads to nonspherocytic
hemolytic disease ([32]1, [33]2). In addition, the serum activity of
PGI has been established as a tumor marker in human cancer patients
([34]3, [35]4), and elevation in PGI activity is closely correlated
with metastasis ([36]5, [37]6).
Recently, it has been shown that several important proteins,
neuroleukin (NLK; refs. [38]7[39]9), autocrine motility factor (AMF;
refs. [40]10 and [41]11), and maturation factor (MF; refs. [42]11 and
[43]12), are closely related, if not identical, to PGI. Mouse and human
NLKs can be aligned with pig muscle PGI without any sequence insertions
or deletions. Including conservative substitutions, mouse NLK has 87%
and 90% sequence identity with human NLK ([44]8) and pig muscle PGI
([45]7), respectively. The primary structural differences are mostly
conservative substitutions that probably reflect species and organ
specificities.
NLK is a neurotrophic growth factor. It promotes motor neuron
regeneration in vivo, fosters the survival of peripheral and central
neurons in vitro, and affects B cell Ig synthesis ([46]13, [47]14).
Interestingly, the dimeric form of NLK carries out its isomerase
activity, whereas the monomeric form of the protein is responsible for
the neurotrophic activity ([48]9). In the presence of monomeric PGI,
neuroblastoma cells have enhanced neurite extension and a reduced
proliferation rate ([49]9). These results suggest that PGI has a growth
factor-like activity and that PGI is potentially related to NLK.
AMF ([50]10, [51]15[52]17) represents a class of cytokines: a group of
proteins that control cell growth and differentiation in embryogenesis,
immunity, and inflammation ([53]18). They are produced locally and act
in an autocrine or paracrine manner. AMF was identified originally by
its ability to induce directed random migration of cells. It has since
been implicated in stimulating motility during cell invasion and
metastasis ([54]10, [55]15).
AMF regulates growth and motility by a receptor-mediated signaling
pathway. On signal transduction, AMF binds to a cell surface
glycoprotein of 78 kDa ([56]19[57]21), implying that AMF is the
natural ligand of the 78-kDa glycoprotein ([58]17). AMF secreted by
Gc-4 PF murine fibrosarcoma cells ([59]10) has PGI activity, whereas
rabbit heart PGI can stimulate mouse fibrosarcoma cell motility similar
to that of endogenous AMF. More importantly, two specific PGI
inhibitors, 6-phosphogluconic acid and erythrose 4-phosphate, can
inhibit the isomerase activity of PGI ([60]22) and abolish the
AMF-induced cell motility ([61]10). The results support the notion that
murine AMF is a PGI.
MF mediates the differentiation of human myeloid leukemic HL-60 cells
to terminal monocytic cells ([62]12). Interestingly, the purified MF
has been shown to have PGI enzymatic activity, and the purified PGI
also has the differentiation property for leukemia cells ascribed to
the MF ([63]12). The amino acid sequence of a tryptic and the enzyme
cleavage sites of MF is 100% homologous to both NLK and PGI ([64]12).
Although studies on PGI have proved a close enzymatic relationship with
NLK, AMF, and MF, nothing is known about the structural basis of these
activities. Previously, we have reported the expression of two Bacillus
stearothermophilus PGIs (PGI-A and PGI-B) in Escherichia coli ([65]23).
In this study, we show that Bacillus PGI stimulates the cell motility
of CT-26 mouse colon tumor cells and enhances the neurite outgrowth on
neuronal progenitor cells. We also present the crystal structure of
PGI-B at 2.3-Å resolution by x-ray diffraction.
[66]Previous Section[67]Next Section
§2§ MATERIALS AND METHODS §2§
§3§ Crystallization and Structure Determination. §3§
The isolation, purification, and crystallization of PGI have been
reported ([68]23). Crystals were grown by the hanging-drop
vapor-diffusion method from solutions containing ammonium phosphate as
the precipitant. The crystals belong to space group I222 with the cell
dimensions a = 75.1 Å, b = 93.7 Å, and c = 171.9 Å; one molecule per
asymmetric unit. After an extensive search, two useful derivatives,
KAu(CN)[2] and HgI[2], were obtained by soaking native crystals in
heavy-atom solutions. All data used for structure determination were
collected on a Rigaku (Tokyo) R-Axis II Imaging Plate mounted on a
Rigaku RU300 rotating-anode. The data were indexed, integrated, and
scaled by using denzo and scalepack (ref. [69]24; Table [70]1).
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Table 1
X-ray crystallography data
The heavy-atom positions were located by difference Patterson
techniques and refined by using the CCP4 (Collaborative Computational
Project, November 4, 1994) implementation of mlphare ([73]24). The
isir-isas program ([74]25) was used to generate the initial miras
(multiple isomorphous replacement including anomalous scattering)
phases at 3.5-Å resolution followed by phase extension to 3.0 Å. The
resulting electron-density map showed a molecular boundary indicative
of a two-domain structure and evidence of several α-helices and β-sheet
strands in both domains. The initial miras phases were improved further
by the program dm ([75]26) by using a combination of solvent
flattening, histogram mapping, and Sayres equation (skeletonization
was not included in this calculation). The miras map showed continuous
electron density with well defined side chains for almost the entire
molecule. The initial model, which contained 440 residues and 3,508
nonhydrogen atoms, resulted in a conventional R factor of 39.8% from 8
Å to 2.8 Å with 2σ(F).
The model was refined against data between 8.0 Å and 2.3 Å by simulated
annealing and positional refinement by using the program x-plor 3.1
([76]27). Individual atoms were assigned isotropic B factors, which
were refined during the latter stages of the refinement. Fig. [77]1
shows a sample final omitted (2F [o]  F [c]) map. The final model
contains 3,699 nonhydrogen atoms, including 184 oxygen atoms from water
molecules. The first and the last two amino acid residues are
presumably disordered in the crystal structure. The R factor is 18.5%
for all 2σ(F) data between 8.0-Å and 2.3-Å resolution. By using a 10%
reflection test set (2,319 reflections), the R [free]-value ([78]28) is
25.8%. The model has good stereochemistry with rms deviations in bond
lengths and angles of 0.012 Å and 1.348°, respectively. Analysis of the
Ramachandran plot ([79]29) shows no violations of accepted backbone
torsion angles. Atomic coordinates have been deposited with the Protein
Data Bank (ref. [80]30; ID code [81]2PGI).
[82]Figure 1
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Figure 1
The omitted 2F [o]  F [c] electron density map of PGI from regions of
the proposed substrate-binding site. The map was calculated by omitting
Lys-139, Glu-285, His-306, and Lys-420 from the x-ray model.
Simulated-annealing refinement was performed with a 3-Å spherical shell
of fixed atoms surrounding the omitted regions and was contoured at the
1.0-σ level. Residues His-306′ and Ser-307′ belong to the
symmetry-related subunit in a dimer.
§3§ Cell-Motility Assay. §3§
Cell motility of mouse CT-26 cells was measured by the method described
by Lin et al. ([86]31) with minor modifications.
Polyvinylpyrrolidone-free polycarbonate filters (Nuclepore; 8-μm pore
size) were soaked in 0.5 M acetic acid overnight. The filters were
washed with distilled water and coated with 50 μl of matrigel for 2 h.
Cells were placed on the top of a Boyden chamber at a cell dose of 5 ×
10^4 per 200 μl in MEM with 10% FBS. Incubation was carried out at 37°C
for 8 h. The filters were removed and fixed in 4% paraformaldehyde for
15 min at room temperature. Cells on the upper filter surface were
removed carefully with a cotton swab. The filters were stained with
hematoxylin for 40 min. Cells on the lower filter surface were counted
under a light microscope.
§3§ Neurite-Outgrowth Assay. §3§
Morphological responses to PGI of rat epidermal growth factor
(EGF)-responsive neuronal embryonic progenitor cells ([87]32, [88]33)
were assayed. The serum-free culture medium was made up of an equal
mixture of DMEM and F-12 nutrient (GIBCO), supplemented with insulin
(25 μg/ml), transferrin (50 μg/ml), progesterone (20 nM), putrescine
(100 μM), and selenium chloride (30 nM). Brains were removed from
17-day-old SpragueDawley rat embryos and dissociated mechanically with
a fire-polished Pasteur pipette. After culturing for 45 days in the
serum-free medium supplemented with 20 ng/ml EGF, the primary
EGF-responsive embryonic neuronal progenitor cells were dissociated
into single cells. The cells were then transferred to 96-well plates
and cultivated in the serum-free medium supplemented with EGF (10
ng/ml) in the presence or absence of PGI.
[89]Previous Section[90]Next Section
§2§ RESULTS AND DISCUSSION §2§
§3§ The Overall Structure. §3§
The overall folding of a PGI monomer is shown in Fig. [91]2. The
molecule is divided clearly into two globular domains (designated as
large and small domains) and an arm-like C-terminal tail. Both the
large and the small domain have a central core of a β-pleated sheet
flanked by α-helices to form a typical α/β folding motif. The large
domain also contains a protruding loop region diametrical to the
C-terminal tail. Therefore, the overall shape of the subunit is
somewhat ellipsoidal with an arm-like structure on each side.
[92]Figure 2
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Figure 2
A ribbon drawing ([96]64, [97]65) of the PGI monomer with the small
domain on the top, the large domain on the bottom, and the C-terminal
domain on the left. α-Helices are colored gold and labeled α1α18.
β-Strands are in green and labeled β1β12. The proposed
substrate-binding site is indicated by an asterisk. The
crystallographic 2-fold axis that runs through the dimer is shown by an
arrow.
The secondary structure of the large domain containing the N-terminal
of the protein is built from two separate peptide segments (residues
234 and 236403). This domain has two antiparallel strands (β10 and
β11) that are placed roughly perpendicularly to a central five-stranded
β-sheet (β1, β7, β8, β9, and β12). Consequently, β10 and β11 form an
arm-like protruding loop. There are two (α14 and α15) and three
α-helices (α12, α13, and α16) on either side of the central
five-stranded β-sheet. From the α3 helix, the chain progresses to form
the entire supersecondary structure of the small domain.
The small domain encompasses residues 56217. It has also a
five-stranded β-sheet (β2, β3, β4, β5, and β6) at the core. The β-sheet
is sandwiched by three helices on one side (α4, α5, and α10) and four
α-helices on the other (α6, α7, α8, and α9), forming a typical open
twisted α/β folding structure. Lastly, the C-terminal 32 amino acids
(residues 414445) of the protein fold into two consecutive helices
(α17 and α18) linked by a short turn.
Because the large domain is built from two separate peptide segments,
it is connected to the small domain by two helices, α3 (residues 4351)
and α11 (residues 220236). Despite the discontinuity in the large
domain, the sheet topologies are similar in both domains. All the
β-strands in both domains are parallel, except for the β1 and the
protruding loop (β10 and β11) in the large domain, which are
antiparallel. The β-strands of the small domain point toward the
C-terminal tail, whereas those from the large domain are oriented
antiparallel to those of the small domain and point toward the
protruding loop region. The arrangement of the small globular domain
and the C-terminal tail results in a slight cleft wherein the substrate
might be bound.
The functional form of the PGI is a dimer. However, there is only a
single subunit in the crystallographic asymmetric unit. The dimer is
globular in shape with dimensions of ≈78 Å × 75 Å × 50 Å. The subunits
associate in an arm-to-arm hug fashion with intimate contacts and form
a hydrophilic channel that coincides with the crystallographic 2-fold
axis that runs through the dimer as indicated by an arrow in Fig.
[98]2. Most of the monomermonomer interactions are formed among
helices and loops, because the β-sheets are in the cores and sandwiched
by helices. Intersubunit contacts are constituted mainly among β2, α6,
α7, α9, α13, α14, α15, α17, α18, and the loop regions. The dimer is
stabilized by a total of 76 intermolecular hydrogen bonds (≤3.5 Å) as
well as van der Waals interactions.
§3§ Structure Comparison with Other Isomerases. §3§
A crystal structure of pig muscle PGI was previously determined at
3.5-Å resolution ([99]34, [100]35). However, because of the resolution
limit and the lack of sequence information, the C[α] backbone of pig
PGI could not be traced throughout the whole structure and not all the
amino acid side chains could be defined. In that model, 85% of the C[α]
atoms were built, and both the N and the C termini were assigned
tentatively. Pig PGI is a dimeric enzyme and reportedly has an α/β
folding motif. Each subunit consists of a large and a small domain. The
large domain contains a six-stranded parallel β-sheet surrounded by
α-helices. The small domain contains a four-stranded parallel
β-structure surrounded by helices and an irregularly folded chain.
Similar to the PGI structure of B. stearothermophilus, the subunit is
somewhat ellipsoidal, and a slight cleft is observed between the two
domains.
It is interesting to compare the three-dimensional structure of PGI
with the structures of triose phosphate isomerase (TPI; ref. [101]36)
and d-xylose isomerase ([102]37[103]39). TPI catalyses the
interconversion between d-glyceraldehyde-3-phosphate and
dihydroxyacetone phosphate ([104]36), whereas xylose isomerase is
involved in the transposition of xylose to xylulose. A
hydride-transfer mechanism has been proposed for xylose isomerase
([105]40[106]43). However, biological and biochemical studies
([107]38, [108]44) suggest that both PGI and TPI use instead a
proton-transfer mechanism. The proton-transfer mechanism involves the
formation of an cis-enediol intermediate by transferring a proton
between C1 and C2 of the sugar ring. Although different mechanisms
pertain to the triose phosphate and the xylose isomerization reactions,
both enzymes form the typical eight-stranded α/β barrel (TIM barrel)
motif structure. In contrast, the PGI model from B. stearothermophilus
has an open twisted α/β structure.
§3§ PGI Stimulates Cell Motility. §3§
Rabbit PGI has been shown to induce directed random migration of tumor
cells and implicated as an AMF ([109]10, [110]17). Results from amino
acid sequencing analysis and immunological cross-reactivity also
suggest that mouse AMF is identical or closely related to PGI/NLK.
Whether B. stearothermophilus PGI has AMF activity can be addressed
directly by observing its migratory-stimulation activity in
cell-motility assays. Purified PGI from B. stearothermophilus
stimulates CT-26 mouse colon cancer cell motility in a dose-dependent
fashion and exerts maximal stimulating activity between 10 pg/ml and
100 pg/ml. Fig. [111]3 is a pictorial demonstration of the motility
assay and the stimulatory effect on CT-26 cells in the absence (Fig.
[112]3 A) or presence (Fig. [113]3 B and C) of PGI. The results are
consistent with those observed by Watanabe et al. ([114]10).
[115]Figure 3
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Figure 3
Dose-dependent motility stimulation of CT-26 mouse colon cancer cells
by purified B. stearothermophilus PGI. CT-26 cells were plated in
culture medium in the absence or various concentrations of PGI.
Representative photomicrographs of cells plated in the absence (A) or
presence of 10 pg/ml (B) or 100 pg/ml (C) PGI are shown.
§3§ Identification of a Putative Substrate-Binding Site of PGI/AMF. §3§
After finding that Bacillus PGI is functionally equivalent to AMF, the
next obvious issue is to locate the substrate-binding site on PGI/AMF.
Because PGI and AMF share the same substrate and inhibitors (i.e.,
carbohydrate phosphates; ref. [119]10), the implicated binding site
should also be the same for both proteins.
The genes coding for PGI have been isolated from a variety of sources
ranging from bacteria to mammals ([120]35, [121]45[122]47). Two
regions of conserved amino acids,
[LIVM]-G-G-R-[FY]-S-[LIVM]-x-[ST]-A-[LIVM]-G and
[FY]-D-Q-x-G-V-E-x-x-K, have been identified (Fig. [123]4) and are
documented as signature patterns for the PGI ([124]48) superfamily.
Members of this superfamily include B. stearothermophilus PGI, pig
muscle PGI, human PGI/NLK/AMF, and mouse PGI/NLK. Residues inside the
square brackets above represent the evolutionarily conserved residues.
The corresponding regions are residues 198210 from the small domain
and 411420 from the large domain in B. stearothermophilus PGI.
Interestingly, these two conserved regions are located within the
slight cleft area in our model. Therefore, it is reasonable to propose
that all PGIs have the same evolutionary origin and employ the same
catalytic mechanism.
[125]Figure 4
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Figure 4
Multiple sequence alignment of the PGI superfamily. Amino acid
sequences of Bacillus PGI-B, Bacillus PGI-A, and PGI from pig, human,
and mouse were aligned. Residues that are identical among all five
sequences are highlighted in red. Positions of deletions are indicated
by dashes. Two signature patterns
([LIVM]-G-G-R-[FY]-S-[LIVM]-x-[ST]-A-[LIVM]-G and
[FY]-D-Q-x-G-V-E-x-x-K) of the PGI superfamily are colored in green.
Amino acids that form the putative substrate-binding sites are denoted
by asterisks.
A base-catalyzed mechanism has been proposed for the interconversion of
aldose and ketose via a cis-enediol intermediate ([129]49, [130]50).
Based on chemical modification and affinity-labeling experiments,
histidine ([131]51), lysine ([132]52), glutamate ([133]53), and
arginine ([134]54) residues have been postulated to be involved in the
catalytic process. Results from site-directed mutagenesis and kinetic
studies ([135]47) also suggested that Lys-139, Arg-202, Lys-289, and
Lys-420 are located in the active site of the B. stearothermophilus
PGI. As determined by the crystallographic studies of pig ([136]34,
[137]35) and rabbit PGIs ([138]2), the active site is situated in a
cleft between the large and small domains of the monomer and is formed
by the association of the two subunits. Their results showed that
histidine and glutamate residues might be situated in the active site
of PGI. Kugler et al. ([139]2) also pointed out that the histidine
residue involved in enzymatic reaction is from the other subunit.
Moreover, the involvement of lysine and arginine residues in the
binding of phosphate groups by various enzymes, such as
6-phosphofructo-2-kinase ([140]55, [141]56), glycogen phosphorylase b
([142]57), maltodextrin phosphorylase ([143]58), protein tyrosine
phosphatase 1B ([144]59), and protein phosphatase 1 ([145]60), have
been well studied.
Based on the substrate-free PGI structure described in this work,
together with the aforementioned biological and biochemical results, we
carried out molecular-modeling studies. A possible binding-site
geometry that may exist in a PGI-substrate (glucose-6-phosphate)
complex was generated by minimizing the distance and neutralizing the
opposite charges between the enzyme and the target substrate. A
speculative model showing how glucose-6-phosphate could be docked into
the putative PGI substrate-binding site is presented in Fig. [146]5.
The possible substrate-binding site of PGI is a deep binding pocket
located between the large domain, the small domain, and the C-terminal
tail.
[147]Figure 5
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Figure 5
A ribbon drawing ([151]64, [152]65) showing the proposed
substrate-binding site as determined by the substrate-free PGI
structure. The glucose-6-phosphate is represented by balls and sticks
and is colored in red (oxygen), deep blue (carbon) and magenta
(phosphorus). The residues potentially involved in the enzymatic
reaction are labeled by name.
The isomerization reaction is initiated by a ring-opening step,
followed by a proton-transfer process and a ring-closure procedure. In
this postulated complex model, Arg-202, Glu-285, and His-306
participate in the catalytic process. Lys-139 forms three salt bridges
with the phosphate group to stabilize the substrate. Glu-417, Tyr-419,
and Lys-420 interact with the hydroxyl groups of C3 and C4 of the
substrate via hydrogen bonds. Glu-285 and His-306 are the two most
likely candidates for the base-catalytic and proton-transfer steps in
the phosphoglucose isomerization. It is interesting to point out that
the His-306 positioned in this possible binding site is from the other
subunit of the dimer. This positioning may explain why the active form
of the isomerase is a dimer. All these important residues, except
Tyr-419, are conserved in the multiple sequence alignment (Fig.
[153]4). Certainly, crystal structures of the
substrate/inhibitor-enzyme complex definitely are needed before the
role of these residues can be defined explicitly.
§3§ PGI Enhanced Neurite Outgrowth. §3§
Many studies ([154]7, [155]8, [156]10, [157]61) have shown that PGI has
a close functional relationship with NLK. Three different hypotheses
were raised by Gurney (as described in ref. [158]8) to explain the
potential relationship between PGI and NLK: (i) the enzymatic activity
of PGI may account for the biological response to NLK; (ii) PGI may act
as a carbohydrate-binding rather than receptor-binding ligand to
trigger the biological response to NLK; and (iii) either PGI or a
processed version of it may be a ligand for a cellular receptor.
To verify that PGI from B. stearothermophilus has neurotrophic
activity, we examined the morphological response to PGI administration
by using rat EGF-responsive neuronal embryonic progenitor cells
([159]32, [160]33). Compared with controls (Fig. [161]6 A), the neurite
extensions in these neuronal progenitor cells were significantly
greater in number and longer in length when treated with PGI (Fig.
[162]6 BD). The results are consistent with the neurotrophic
activities observed by Gurney et al. ([163]62) and Mizrachi ([164]9)
and confirmed that PGI is NLK.
[165]Figure 6
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Figure 6
Morphological response of rat EGF-responsive neuronal embryonic
progenitor cells promoted by PGI. (A) After 4 days of cultivation in
the absence of PGI, the neuronal progenitor cells formed a single
sphere of undifferentiated morphology, compared with a differentiated
morphology of neurite outgrowth treated with 2 ng/ml PGI (B), 20 ng/ml
PGI (C), and 200 ng/ml PGI (D).
To identify the regions on PGI that are responsible for NLK activity,
we carried out a molecular-surface study on our PGI model. Fig. [169]7
shows the electrostatic surface potential of the B. stearothermophilus
PGI monomer displayed by the program grasp ([170]63). The negatively
charged surface (potential < 10 kT) is displayed in deep red, whereas
the positively charged surface (potential > 10 kT) is in deep blue. The
surface potential of the small domain and the C-terminal region is more
neutral and is depicted mostly in white. We have proposed in the last
section that the substrate-binding site for PGI/AMF is most likely
seated in the junction where the large domain, small domain, and the
C-terminal tail come together. In contrast, a strong acidic region is
found on the top half of the large domain and the protruding loop
(residues 329352). These distinctive surface-potential regions may be
responsible for the NLK activity of PGI. Moreover, Mizrachi ([171]9)
reported that a synthetic peptide covering residues 401421 of the
rabbit NLK has cell proliferative activity. In our PGI model, the
corresponding residues are 319339 and located in β10 and the
protruding loop. We tentatively proposed that the top part of the large
domain and the protruding loop may play another biological function,
such as the neurotrophic activity. However, these speculations need to
be confirmed by further neurobiological and biochemical study.
[172]Figure 7
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Figure 7
Electrostatic surface potential on the PGI molecule displayed with the
program grasp ([176]63). Negative potentials (<10 kT) are colored in
deep red, and positive potentials (>10 kT) are colored in deep blue.
The neutral surface potential regions are depicted in white. The
orientation of the molecule is the same as in Fig. [177]2.
[178]Previous Section[179]Next Section
§2§ CONCLUSIONS §2§
In the present study, we determined the three-dimensional structure of
PGI from B. stearothermophilus at 2.3-Å resolution by x-ray
crystallography. We also demonstrated by cell-migratory stimulation and
neurotrophic-activity experiments that PGI has AMF and NLK activities.
A putative substrate-binding site is proposed for further
investigation. Our x-ray studies implicate several residues as
important in the catalytic reaction. In addition, the structure
provides evidence to suggest that the top part of the large domain and
the protruding loop may participate in inducing neurotrophic activity
for PGI/NLK. However, many questions, such as how PGI exerts its effect
on nerve cells; how PGI performs its cell-motility activity; and how
PGI switches its enzymatic and biological functions, remain unanswered.
The complete high-resolution structure of PGI presented here offers a
starting point for further crystallographic, biochemical, genetic, and
neurobiological studies of PGI/NLK/AMF. The structure also provides a
framework for understanding the structure of other PGI/NLK/AMFs from
the same superfamily.
[180]Previous Section[181]Next Section
§2§ Acknowledgments §2§
We are grateful to Dr. M. F. Tam of the Institute of Molecular Biology,
Academia Sinica for helpful discussions. This work was supported in
part by National Science Council Grant NSC87-2311-B-001-025-B21 (to
C.-D.H.), Republic of China.
[182]Previous Section[183]Next Section
§2§ Footnotes §2§
* [184]↵ ‖ To whom reprint requests should be addressed.
e-mbhsiao{at}ccvax.sinica.edu.tw.
* This paper was submitted directly (Track II) to the Proceedings
Office.
* Data deposition: The atomic coordinates have been deposited in the
Protein Data Bank, Biology Department, Brookhaven National
Laboratory, Upton, NY 11973 (PDB ID code [185]2PGI).
* ABBREVIATIONS:
PGI,
phosphoglucose isomerase;
AMF,
autocrine motility factor;
NLK,
neuroleukin;
MF,
maturation factor;
EGF,
epidermal growth factor
* Copyright © 1999, The National Academy of Sciences
[186]Previous Section
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