Crystal structure of the catalytic domain of DESC1, a new
member of the type II transmembrane serine proteinase
family
Otto J. P. Kyrieleis
1,
*, Robert Huber
1,2
, Edgar Ong
3
, Ryan Oehler
3
, Mike Hunter
3
,
Edwin L. Madison
3
and Uwe Jacob
1,

1 Max-Planck-Institut fu
¨
r Biochemie, Martinsried, Germany
2 Cardiff University, UK
3 Corvas International, San Diego, CA, USA
DESC1 is a type II transmembrane serine proteinase
(TTSP), an expanding protein family with members
differentially expressed in several organs and certain
tumors. To date, more than 30 mammalian members of
this group have been identified and have, according to
their sequence similarity, been grouped into four sub-
families: DESC ⁄ human airway trypsin (HAT) ⁄ HAT-

expanding family of serine proteinases, whose members are differentially
expressed in several tissues. The biological role of these proteins is cur-
rently under investigation, although in some cases their participation in
specific functions has been reported. This is the case for enteropeptidase,
hepsin, matriptase and corin. Some members, including DESC1, are associ-
ated with cell differentiation and have been described as tumor markers.
TTSPs belong to the type II transmembrane proteins that display, in addi-
tion to a C-terminal trypsin-like serine proteinase domain, a differing set of
stem domains, a transmembrane segment and a short N-terminal cytoplas-
mic region. Based on sequence analysis, the TTSP family is subdivided into
four subfamilies: hepsin ⁄ transmembrane proteinase, serine (TMPRSS);
matriptase; corin; and the human airway trypsin (HAT) ⁄ HAT-like ⁄ DESC
subfamily. Members of the hepsin and matriptase subfamilies are known
structurally and here we present the crystal structure of DESC1 as a first
member of the HAT ⁄ HAT-like ⁄ DESC subfamily in complex with benza-
midine. The proteinase domain of DESC1 exhibits a trypsin-like serine pro-
teinase fold with a thrombin-like S1 pocket, a urokinase-type plasminogen
activator-type S2 pocket, to accept small residues, and an open hydro-
phobic S3 ⁄ S4 cavity to accept large hydrophobic residues. The deduced
substrate specificity for DESC1 differs markedly from that of other struc-
turally known TTSPs. Based on surface analysis, we propose a rigid
domain association for the N-terminal SEA domain with the back site of
the proteinase domain.
Abbreviations
HAI, hepatocyte growth factor activator inhibitor; HAT, human airway trypsin; PAI-1, plasminogen activator inhibitor 1; PCI, protein C
inhibitor; SRCR, scavenger receptor cystein-rich; TMPRSS, transmembrane proteinase, serine; TTSP, type II transmembrane serine
proteases; uPA, urokinase-type plasminogen activator.
2148 FEBS Journal 274 (2007) 2148–2160 ª 2007 Max-Planck-Insitute of Biochemistry Journal compilation ª 2007 FEBS
type (matriptase 1–3 and polyserase); hepsin ⁄ trans-
membrane proteinase, serine (TMPRSS) type (hepsin ⁄

was restricted to normal epithelial cells of prostate,
skin, testes, head and neck, whereas it was downregu-
lated or absent in the corresponding cells of squamous
cell carcinoma of the head and neck [4]. It has therefore
been proposed as a possible tumor marker. Further-
more, Sedghizadeh et al. [5] were able to show that
DESC1 is upregulated during the induction of terminal
keratinocyte differentiation, supporting a role in nor-
mal epithelial turnover. These results suggest that
DESC1 may function in regular epithelial differenti-
ation under normal conditions or in circumventing
tumorigenesis under cancer-promoting conditions.
Recently, the mouse ortholog of DESC1 was identified,
and was found to have 72% shared identity with
human DESC1. Both proteinases are expressed in
similar anatomical locations and are likely to have
common functions in the development and maintenance
of oral epidermal tissues and the male reproduction
tract [6].
Human DESC1 has a short 20-amino acid cytoplas-
mic region followed by 14 residues of a putative trans-
membrane region. The extracellular part of DESC1
consists of a 120-amino acid SEA domain followed by
the C-terminal trypsin-like serine proteinase domain,
as shown in Scheme 1.
DESC2 and DESC3 were subsequently identified by
database searches [2]. In contrast to DESC1, many
TTSPs are overexpressed by tumor cells (e.g. matrip-
tase, hepsin). The frequent association between cancer
and TTSP expression suggests that development of

. The highest topological
similarity to DESC1 is seen with hepsin (r.m.s.d ¼
0.70 A
˚
) with 229 Ca atoms of topologically equivalent
residues, of which 96 are topologically identical. The
next best fit is found with matriptase and enteropeptidase,
Scheme 1. Domain organization of human DESC1.
O. J. P. Kyrieleis et al. Crystal structure of the catalytic domain of DESC1
FEBS Journal 274 (2007) 2148–2160 ª 2007 Max-Planck-Insitute of Biochemistry Journal compilation ª 2007 FEBS 2149
both with r.m.s.d. values of 0.75 A
˚
. Matriptase shares
111 topologically identical residues with DESC1,
whereas enteropeptidase has 87 topologically identical
residues. The topological equivalence of the four
TTSPs forms the basis for the sequence alignment
shown in Fig. 3. The numbering in the alignment
refers to the chymotrypsin numbering. Despite the
high topological similarity found among these protein-
ases, significant differences exist within the loop struc-
tures that confer specificity to the enzymes for the
interactions with the differing substrates and binding
partners. These loop regions surround the active site
and are named according to the residue in the mid-
point of the respective loop, as shown in Fig. 2. To
the east of the active site the 37- and 60-loops border
the S2¢ pocket of the proteinase. The observed differ-
ences in the 37-loop result from interactions between
the differing side chains in this region, which directly

Glu70 and Glu80. The first half (71–75) (Fig. 3) of this
loop is deleted in DESC1. Val70 and Lys80 replace the
calcium-binding residues in DESC1. Whereas in the
other TTSPs, residue 80 is hydrophobic and interacts
Fig. 1. Stereo ribbon representation of
DESC1 in complex with benzamidine
(white). The residues of the catalytic triad
are shown in ball and stick form (Ser195,
His57 and Asp102). The termini are labeled
and hydrogen bonds are shown as yellow
dashed lines. The figure was generated
using
MOLSCRIPT [30] and RASTER3D [31].
Fig. 2. DESC1 (light blue) superimposed
with the catalytic domains of human matrip-
tase (yellow) (9), human enteropeptidase
(red) (8) and human hepsin (dark blue) (7).
The active site residues of DESC1, Asp189
and the bound benzamidine are shown as
ball-and-stick models. The termini and the
important loops discussed in the text are
labeled. The figure was generated using
MOLSCRIPT [30] and PYMOL [32].
Crystal structure of the catalytic domain of DESC1 O. J. P. Kyrieleis et al.
2150 FEBS Journal 274 (2007) 2148–2160 ª 2007 Max-Planck-Insitute of Biochemistry Journal compilation ª 2007 FEBS
with its counterpart in position 70, the DESC1 Lys80
points in the opposite direction to interact with the
carboxylate group of Glu24.
Active site
At first glance, the structures of the four TTSPs appear

selective small-molecule inhibitors that may represent
an interesting new class of anticancer compounds.
The following analysis of the active site pockets and
the key residues is based on the structurally solved
members of the TTSP subfamilies. Within the indi-
vidual subfamilies these residues are not conserved,
leading to even more pronounced diversification.
Detailed sequence-based information on all TTSPs can
be obtained from the recent comprehensive reviews
[1,2,10].
S1
The following segments border the S1-specificity pocket
of DESC1: Asp189–Gln192 (the basement of the
pocket), Ser214–Gly219 (the entrance frame), Lys224–
Tyr228 (the back of the pocket) and the disulfide bridge
Cys191–Cys220 (the front of the pocket) (Fig. 4A). The
backbones of these segments form a deep hydrophobic
pocket with the negatively charged Asp189 at its bot-
tom. Asp189 at the bottom of the pocket determines
the specificity of the S1 pocket for basic residues Arg
and Lys at position P1 of the substrate. Consequently,
in the DESC1 complex structure the bound benza-
midine points with its amidino group towards the carb-
oxylate group of Asp189 forming the canonical
two-O ⁄ two-N salt bridge. One additional hydrogen
bond is found between the amidinonitrogen and the
Asp219 carbonyl oxygen. The peptide planes of the
bonds between Trp215–Gly216 and Cys191–Gln192
sandwich the phenyl ring of benzamidine. The
DESC1 S1 pocket resembles the thrombin S1 pocket

almost closed (Fig. 4B) and there will be a strong pref-
erence for glycine in the corresponding substrate resi-
due. DESC1 may accommodate alanine residues as
stated, is wide open and shaped as a rather shallow
depression with no exact borders. In hepsin (Fig. 4C)
the 99-position is occupied by asparagine, which is
markedly pulled out of the active site, so that the S2
site merges directly into the S3 ⁄ S4 site. Compared with
the other TTSPs hepsin displays the largest S2 site giv-
ing space for bulky polar residues that can interact
with the carbonyl oxygen as well as with the amino
group of Asn99. In comparison with hepsin in entero-
peptidase (Fig. 4D) Lys99 clearly separates the S2 and
S3 ⁄ S4 subsites. Whereas DESC1, matriptase and hep-
sin are shown in Fig. 4A–C complexed with benza-
midine (DESC1 and matriptase) and with a derivative
of benzamidine (hepsin), enteropeptidase is shown
in complex with the trypsinogen-activation peptide
Val-(Asp)
4
-Lys-chloromethylketone. The synthetic benz-
amidine-based inhibitors of DESC1, matriptase and
hepsin display nicely the interaction of the S1 site, but
do not interact with the S2 site of these proteinases.
By contrast, the aspartates in positions P2 and P3 of
the chloromethylketone occupy the S2 and S3 ⁄ S4 cav-
ity in enteropeptidase. Moreover, the side chain of
Lys99 separates both cavities, generating specificity for
these acidic residues in position P2 as well as in posi-
tion P3 ⁄ P4 (Fig. 4D).

sentation. All inhibitors are represented in
ball-and-stick models in black. Residues
discussed in the text are labeled, and hydro-
gen bonds are drawn as dashed black lines.
The figure was generated using
GRASP [36]
and
PYMOL [32].
O. J. P. Kyrieleis et al. Crystal structure of the catalytic domain of DESC1
FEBS Journal 274 (2007) 2148–2160 ª 2007 Max-Planck-Insitute of Biochemistry Journal compilation ª 2007 FEBS 2153
limits the S3 ⁄ S4 pocket. In comparison with DESC1,
the matriptase and hepsin S3 ⁄ S4 pockets are signifi-
cantly smaller because of the Ala175Gln substitution.
Structural distinctions among these three TTSPs in
the 174-loop, combined with the presence of differing
residue 99s (His ⁄ DESC1, Phe ⁄ matriptase, Asn ⁄ hepsin,
Lys ⁄ enteropeptidase) that line the S3 ⁄ S4 pocket to the
east, suggest clearly distinct P3 preferences for sub-
strate and inhibitor recognition. DESC1 prefers large
hydrophobic residues with the capability to interact
specifically with His99 to the east at P3. Similar to
DESC1, and because of the presence of Phe99, matrip-
tase binds preferably large hydrophobic residues at P3,
but with the difference that these residues are able to
interact specifically with Gln175 to the west. By con-
trast to DESC1 and matriptase, the S3 pocket of hep-
sin is best suited for polar interactions to the west
(Gln175) and east (Asn99). In enteropeptidase, this
pocket is very narrow because of the tyrosine at posi-
tion 174a and Lys99, but, depending on the residue

observed conformation of Tyr149 in DESC1, the
entrance to the active site is significantly restricted
from the south, but this residue is completely solvent
exposed and may rotate out of the way during interac-
tion with bigger substrates. The exposed hydroxy-
phenyl group of Tyr149 might even represent a
secondary binding site for substrates or inhibitors.
Substrate specificity of DESC2, -3, HAT
and HAT-like 4
Comparison of the primary sequences of DESC2, -3,
HAT and HAT-like 4 with DESC1 reveals that the
residues, which confer specificity to subsites S3 ⁄ 4, S2
and S1¢⁄2¢, differ markedly in the members of this sub-
family, as shown in Fig. 3. By contrast, the S1 subsite
is characterized by the conserved residues Asp189 and
Ala190 of the Ala190-type of serine proteases which
prefer Arg to Lys at position P1. Also conserved are
residues Trp215, Lys224 and Trp174 forming the flat
hydrophobic area at the bottom of the S3 ⁄ 4 subsite.
Differences are found in the 174-loop residues, which
represent the interacting partners for P4 residues. In
combination with the different residues for DESC2, -3,
HAT and HAT-like 4 in the 99-position it is therefore
likely that the five known members of this subfamily
have different preferences for residues bound to sub-
sites S3 ⁄ S4 and S2. With regard to the S1¢⁄2¢ subsite,
the residues of the 60-loop mainly determine the sub-
strate specificity. The alignment in Fig. 3 clearly shows
that these residues differ not only in their chemical
nature, but also in the flexibility of the different

side chain of this residue can fill a hydrophobic hole
that is occupied by Leu51 of the SRCR domain in
hepsin (Fig. 5A). This conformation does not seem to
be an artifact of the missing N-terminal domain
because in DESC1, as well as in matriptase, the con-
formation of this residue is stabilized by a salt bridge
of the C-terminal carboxylate group with the guanidyl
group of Arg235. In hepsin the less hydrophobic
Thr244 replaces the Ile244 side chain of DESC1. As
part of the additional loop structure in hepsin, Thr244
is shifted to the north of the hydrophobic interaction
surface so that the Leu51 side chain of the SRCR
domain can bind into the hydrophobic depression.
This interaction is not possible in DESC1 and matrip-
tase because of the above-mentioned position of the
C-terminal Ile244 (DESC1) and Val244 (matriptase).
In DESC1, the exposed Arg120 side chain in the center
of the interaction surface may serve as an interaction
partner for negatively charged residues of the SEA
domain, in addition to interactions of the surrounding
hydrophobic residues. Coloring of the surfaces accord-
ing to hydrophobic and polar residues clearly shows
that the hydrophobic interaction surface positioned at
the backside of the proteinase domain is a conserved
feature of all structural known TTSPs. Moreover,
Fig. 5A shows that the C-terminus of the SCRC
domain runs in a hydrophobic canyon connecting the
left lower part of the hydrophobic interaction surface
with the front site of the molecule. This canyon, as
well as the binding mode of the C-terminus, is also

O. J. P. Kyrieleis et al. Crystal structure of the catalytic domain of DESC1
FEBS Journal 274 (2007) 2148–2160 ª 2007 Max-Planck-Insitute of Biochemistry Journal compilation ª 2007 FEBS 2155
DESC1 ⁄ hepsin, beside the proteinase domain, only a
single SEA or SRCR domain is found, the stem
regions of matriptase and enteropeptidase are extended
to six (matriptase) and seven (enteropeptidase) addi-
tional domains [2]. These additional domains may
represent the interaction partners of the second inter-
action surfaces observed in matriptase (Fig. 5C) and
enteropeptidase (Fig. 5D).
Conclusions
Substrate specificity
The substrate specificity of DESC1’s proteinase domain,
as deduced from the analysis of this crystal structure
with large hydrophobic residues in P4 ⁄ P3, for small res-
idues in P2, Arg or Lys in P1 and hydrophobic residues
in P1¢ and P3¢ is in agreement with the work of Hobson
et al. [6]. The authors found the highest enzymatic
activity of DESC1 with chromogenic substrates con-
taining Ala in positions P4 and P3 and Pro in position
P2, followed by substrates containing Phe and Gly in
positions P3 and P2. Acidic residues in position P3 are
still processed, but with much lower enzymatic activity
[6]. Taken together, the predicted substrate sequence
differs markedly from other known TTSP structures.
This unique fine structure of the binding pockets could
consequently be exploited in a mixture-based peptidic
inhibitor library screen, arrayed in a positional scanning
format (Corvas International, personnel communica-
tion). This screening suggested that DESC1 prefers

regulation of DESC1 involves interaction with Kunitz-
type inhibitors, it is clear that DESC1 exhibits a high
affinity for BPTI (unpublished data), a prototypical
Kunitz domain. Matriptase is efficiently inhibited by
hepatocyte growth factor activator inhibitor (HAI)-1, a
transmembrane protein, which consists of 478 residues
and contains two Kunitz-type domains [14]. Only the
first Kunitz-type HAI-1 has inhibitory properties on
matriptase [9], and, as expected, the reactive center
loop of this Kunitz domain, which is Gly12(I)-
Arg13(I)-Cys14(I)-Arg15(I)-Gly16( I)-Ser17(I)-Phe18( I)
[using the BPTI nomenclature, with Arg15(I) | Gly
16(I) as the scissile bond], matches optimal subsite
occupancy for matriptase relatively well, contributing
to the tight binding of the enzyme [9]. The efficient
inhibition of matriptase by HAI-1 appears to represent
a key regulatory constraint on matriptase activity
in vivo. However, the distinct specificities of matriptase
and DESC1 suggest that it is unlikely that DESC1 is a
physiologically relevant target for HAI-1; neither the
first nor the second Kunitz-type domain match the
reported substrate specificity of DESC1 [14]. Other
Kunitz-type inhibitors present in human plasma include
HAI-2 [15], amyloid b protein precursor [16] and tissue
factor pathway inhibitor [17,18], but the existence
and ⁄ or identity of (the) physiologically relevant inhib-
itor(s) of DESC1 remain uncertain. Another commonly
observed type of inhibition for serine proteinases is the
inhibition by serine proteinase inhibitors (serpins). The
serpins form a family of homologous, large (glyco-)

arginine as P1 residues, which explains why the forma-
tion of a stable inhibitory complexes of these serpins is
not possible with DESC1 [6]. However, predictions of
serpin–proteinase interactions are notoriously difficult
because of the flexible nature of their reactive site seg-
ment and ⁄ or possible exosite binding [21].
Domain structure
Surface analysis of DESC1 suggests a possible rigid
domain association between the N-terminal SEA
domain and the back site of the proteinase domain.
This interaction would fix the SEA domain in a loca-
tion on the opposite side of the proteinase domain
from the active site cleft. It seems very unlikely, there-
fore, that the SEA domain would directly influence the
binding of either substrates or inhibitors into the active
site cleft of the DESC1. Instead, because SEA domains
are proposed to bind O-glucosidic-linked proteoglycans
present in the carbohydrate-rich environments [2,22] of
the extracellular matrix, it seems more likely that the
SEA domain functions by orienting the active site cleft
of DESC1 toward plasma and ⁄ or extracellular spaces
and away from the cell surface and ⁄ or the extracellular
matrix. The SEA domain may also contribute to the
adhesion properties of DESC1-expressing cells and
might localize ‘shed’ DESC1 in appropriate microenvi-
ronments. Corresponding surface analysis of other
structurally investigated TTSPs suggests that rigid
association with at least one N-terminal domain
appears to be a common structural feature of TTSPs.
Moreover, it suggests that orientation of the active site

DESC1 were screened for production of the protein by
assaying conditioned media for enzymatic activity against
Spectrozyme t-PA (CH
3
SO
2
-D-HHT-Gly-Arg-pNA*HCl;
American Diagnostica, Stanford, CT, USA).
Details of the expression and purification of multimilli-
gram amounts of human DESC1 will be published sepa-
rately. Briefly, the protein was expressed in the SMD 1168
strain of P. pastoris using a variant of the pPIC9K vector.
Cells were grown in 5-L fermentation vessels, supernatant
was clarified and collected, and DESC1 was purified by
using affinity chromatography on a benzamidine column
followed by anion exchange chromatography on a Q-Seph-
arose column (Amersham Biosciences, Inc., Piscataway,
NJ, USA) and on a Source 15Q column (Amersham Bio-
sciences). Fractions containing protein were pooled, and
benzamidine was added to a final concentration of 10 mm.
The protein purity was examined by SDS ⁄ PAGE, and the
protein concentration was determined at A
280
(using an
extinction coefficient of 2.012 mgÆA
À 1
280
).
DESC1 ⁄ benzamidine crystals
Cloning, expression and purification yielded milligram

A complete native data set to 1.6 A
˚
resolution was collected
at room temperature from a single crystal of the DESC1–
benzamidine complex mounted on a rotating anode gener-
ator (Rigaku, Tokyo, Japan) equipped with an image plate
detector (Mar Research, Hamburg, Germany). These data
were integrated with the mosflm package [23] and scaled
with scala from the ccp4 [24] program suite (Table 1). To
determine the position of DESC1 molecules within the
asymmetric unit rotation and translation searches were car-
ried out with amore using data from 20 to 3.5 A
˚
, and an
enteropeptidase search model. The best solution had a cor-
relation factor of 0.36 and an R-factor of 0.46; the corres-
ponding values of the next best solution were 0.22 and 0.50.
Crystallographic refinement was carried out over several
cycles consisting of model building performed with O [25–
27] and conjugate gradient minimization and simulated
annealing with the cns [28] program suite, using the target
parameters of Engh and Huber [29]. The refinement proce-
dure leads to a model with excellent parameters (Table 1).
In the final model building ⁄ refinement cycles water mole-
cules were inserted and individual restrained atomic B-val-
ues were refined. We omitted 4.3% of all reflections from
the refinement to calculate the R
free
. The final R and R
free

proenteropeptidase is activated by trypsin, and the spe-
cificity of enteropeptidase depends on the heavy chain.
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Table 1. Data collection and refinement statistics of DESC1. Num-
bers in parentheses are for the outermost shell of the data.
Data collection
Space group P21212
Unit cell dimesions (A
˚
)a¼ 47.9
b ¼ 70.2
c ¼ 80.2
a ¼ b ¼ c ¼ 90°
Wavelength (A
˚
) 1.54
Resolution of data (A

a
Crystallographic R-factor ¼ S
hkl
||F
obs
| ) k|F
calc
|| ⁄S
hkl
|F
obs
|.
b
Free
R-factor ¼ S
hklTest
||F
obs
| ) k|F
calc
|| ⁄S
hklTest
|F
obs
|.
Crystal structure of the catalytic domain of DESC1 O. J. P. Kyrieleis et al.
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