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PDBsum entry 1l2e
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* Residue conservation analysis
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DOI no:
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J Biol Chem
277:24562-24570
(2002)
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PubMed id:
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Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system.
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M.J.Bernett,
S.I.Blaber,
I.A.Scarisbrick,
P.Dhanarajan,
S.M.Thompson,
M.Blaber.
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ABSTRACT
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The human kallikreins are a large multigene family of closely related
serine-type proteases. In this regard, they are similar to the multigene
kallikrein families characterized in mice and rats. There is a much more
extensive body of knowledge regarding the function of mouse and rat kallikreins
in comparison with the human kallikreins. Human kallikrein 6 has been proposed
as the homologue to rat myelencephalon-specific protease, an arginine-specific
degradative-type protease abundantly expressed in the central nervous system and
implicated in demyelinating disease. We present the x-ray crystal structure of
mature, active recombinant human kallikrein 6 at 1.75-A resolution. This high
resolution model provides the first three-dimensional view of one of the human
kallikreins and one of only a few structures of serine proteases predominantly
expressed in the central nervous system. Enzymatic data are presented that
support the identification of human kallikrein 6 as the functional homologue of
rat myelencephalon-specific protease and are corroborated by a molecular
phylogenetic analysis. Furthermore, the x-ray data provide support for the
characterization of human kallikrein 6 as a degradative protease with structural
features more similar to trypsin than the regulatory kallikreins.
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Selected figure(s)
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Figure 5.
Fig. 5. Relaxed stereo ribbon diagrams of hK6 (top
panel), bovine trypsin (1CE5; middle panel), and mouse glandular
kallikrein 13 (mK13) (1AO5; lower panel). Orientation is
intended to show the active site cleft with locations of
catalytic triad (His57, Asp102, and Ser195), S1 site (Asp192),
and bound benzamidine inhibitor (if present). Also indicated are
the locations of the autolysis sites in hK6 and bovine trypsin.
The two canonical autolysis sites in the mouse kallikreins are
indicated using the structure of mK13. Also shown are the
locations of the loop regions 92-102 (blue), 141-152 (magenta),
and 172-178 (green) that border the active site.
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Figure 7.
Fig. 7. Relaxed stereo diagram showing details of the S1
binding pocket in hK6 (upper panel), bovine trypsin (1CE5;
middle panel), and porcine kallikrein (2PKA, lower panel). The
hydrogen bonding interactions of the bound benzamidine inhibitor
are shown using broken lines (residue positions 191-193 are
omitted for clarity).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2002,
277,
24562-24570)
copyright 2002.
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Figures were
selected
by the author.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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R.Ramachandran,
F.Noorbakhsh,
K.Defea,
and
M.D.Hollenberg
(2012).
Targeting proteinase-activated receptors: therapeutic potential and challenges.
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Nat Rev Drug Discov,
11,
69-86.
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A.Pavlopoulou,
G.Pampalakis,
I.Michalopoulos,
and
G.Sotiropoulou
(2010).
Evolutionary history of tissue kallikreins.
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PLoS One,
5,
e13781.
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G.Sotiropoulou,
and
G.Pampalakis
(2010).
Kallikrein-related peptidases: bridges between immune functions and extracellular matrix degradation.
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Biol Chem,
391,
321-331.
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P.Goettig,
V.Magdolen,
and
H.Brandstetter
(2010).
Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs).
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Biochimie,
92,
1546-1567.
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G.Sotiropoulou,
G.Pampalakis,
and
E.P.Diamandis
(2009).
Functional roles of human kallikrein-related peptidases.
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J Biol Chem,
284,
32989-32994.
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A.G.Vandell,
N.Larson,
G.Laxmikanthan,
M.Panos,
S.I.Blaber,
M.Blaber,
and
I.A.Scarisbrick
(2008).
Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines.
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J Neurochem,
107,
855-870.
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A.J.Ramsay,
J.C.Reid,
M.N.Adams,
H.Samaratunga,
Y.Dong,
J.A.Clements,
and
J.D.Hooper
(2008).
Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs).
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Biol Chem,
389,
653-668.
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F.Rückert,
M.Hennig,
C.D.Petraki,
D.Wehrum,
M.Distler,
A.Denz,
M.Schröder,
G.Dawelbait,
H.Kalthoff,
H.D.Saeger,
E.P.Diamandis,
C.Pilarsky,
and
R.Grützmann
(2008).
Co-expression of KLK6 and KLK10 as prognostic factors for survival in pancreatic ductal adenocarcinoma.
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Br J Cancer,
99,
1484-1492.
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H.X.Li,
B.Y.Hwang,
G.Laxmikanthan,
S.I.Blaber,
M.Blaber,
P.A.Golubkov,
P.Ren,
B.L.Iverson,
and
G.Georgiou
(2008).
Substrate specificity of human kallikreins 1 and 6 determined by phage display.
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Protein Sci,
17,
664-672.
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H.Yoon,
S.I.Blaber,
D.M.Evans,
J.Trim,
M.A.Juliano,
I.A.Scarisbrick,
and
M.Blaber
(2008).
Activation profiles of human kallikrein-related peptidases by proteases of the thrombostasis axis.
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Protein Sci,
17,
1998-2007.
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I.A.Scarisbrick,
R.Linbo,
A.G.Vandell,
M.Keegan,
S.I.Blaber,
M.Blaber,
D.Sneve,
C.F.Lucchinetti,
M.Rodriguez,
and
E.P.Diamandis
(2008).
Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration.
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Biol Chem,
389,
739-745.
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J.A.Clements
(2008).
Reflections on the tissue kallikrein and kallikrein-related peptidase family - from mice to men - what have we learnt in the last two decades?
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Biol Chem,
389,
1447-1454.
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J.L.Shaw,
and
E.P.Diamandis
(2008).
Regulation of human tissue kallikrein-related peptidase expression by steroid hormones in 32 cell lines.
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Biol Chem,
389,
1409-1419.
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K.Oikonomopoulou,
K.K.Hansen,
A.Baruch,
M.D.Hollenberg,
and
E.P.Diamandis
(2008).
Immunofluorometric activity-based probe analysis of active KLK6 in biological fluids.
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Biol Chem,
389,
747-756.
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M.Debela,
N.Beaufort,
V.Magdolen,
N.M.Schechter,
C.S.Craik,
M.Schmitt,
W.Bode,
and
P.Goettig
(2008).
Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7.
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Biol Chem,
389,
623-632.
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N.Sharma,
K.Oikonomopoulou,
K.Ito,
B.Renaux,
E.P.Diamandis,
M.D.Hollenberg,
and
D.E.Rancourt
(2008).
Substrate specificity determination of mouse implantation serine proteinase and human kallikrein-related peptidase 6 by phage display.
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Biol Chem,
389,
1097-1105.
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R.S.Henkhaus,
E.W.Gerner,
and
N.A.Ignatenko
(2008).
Kallikrein 6 is a mediator of K-RAS-dependent migration of colon carcinoma cells.
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Biol Chem,
389,
757-764.
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C.A.Borgoño,
J.A.Gavigan,
J.Alves,
B.Bowles,
J.L.Harris,
G.Sotiropoulou,
and
E.P.Diamandis
(2007).
Defining the extended substrate specificity of kallikrein 1-related peptidases.
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Biol Chem,
388,
1215-1225.
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I.S.Fernández,
L.Ständker,
W.G.Forssmann,
G.Giménez-Gallego,
and
A.Romero
(2007).
Crystallization and preliminary crystallographic studies of human kallikrein 7, a serine protease of the multigene kallikrein family.
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Acta Crystallogr Sect F Struct Biol Cryst Commun,
63,
669-672.
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J.Chee,
J.Singh,
A.Naran,
N.L.Misso,
P.J.Thompson,
and
K.D.Bhoola
(2007).
Novel expression of kallikreins, kallikrein-related peptidases and kinin receptors in human pleural mesothelioma.
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Biol Chem,
388,
1235-1242.
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S.I.Blaber,
H.Yoon,
I.A.Scarisbrick,
M.A.Juliano,
and
M.Blaber
(2007).
The autolytic regulation of human kallikrein-related peptidase 6.
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Biochemistry,
46,
5209-5217.
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S.J.Shan,
A.Scorilas,
D.Katsaros,
and
E.P.Diamandis
(2007).
Transcriptional upregulation of human tissue kallikrein 6 in ovarian cancer: clinical and mechanistic aspects.
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Br J Cancer,
96,
362-372.
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A.K.Whitbread,
T.L.Veveris-Lowe,
M.G.Lawrence,
D.L.Nicol,
and
J.A.Clements
(2006).
The role of kallikrein-related peptidases in prostate cancer: potential involvement in an epithelial to mesenchymal transition.
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Biol Chem,
387,
707-714.
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G.Pampalakis,
and
G.Sotiropoulou
(2006).
Multiple mechanisms underlie the aberrant expression of the human kallikrein 6 gene in breast cancer.
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Biol Chem,
387,
773-782.
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I.A.Scarisbrick,
P.Sabharwal,
H.Cruz,
N.Larsen,
A.G.Vandell,
S.I.Blaber,
S.Ameenuddin,
L.M.Papke,
M.G.Fehlings,
R.K.Reeves,
M.Blaber,
A.J.Windebank,
and
M.Rodriguez
(2006).
Dynamic role of kallikrein 6 in traumatic spinal cord injury.
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Eur J Neurosci,
24,
1457-1469.
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N.Heuzé-Vourc'h,
M.Aïnciburu,
C.Planque,
M.Brillard-Bourdet,
C.Ott,
C.Jolivet-Reynaud,
and
Y.Courty
(2006).
Recombinant kallikrein expression: site-specific integration for hK6 production in human cells.
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Biol Chem,
387,
687-695.
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N.Memari,
L.Grass,
T.Nakamura,
I.Karakucuk,
and
E.P.Diamandis
(2006).
Human tissue kallikrein 9: production of recombinant proteins and specific antibodies.
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Biol Chem,
387,
733-740.
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T.Kishi,
S.M.Cloutier,
C.Kündig,
D.Deperthes,
and
E.P.Diamandis
(2006).
Activation and enzymatic characterization of recombinant human kallikrein 8.
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Biol Chem,
387,
723-731.
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G.Laxmikanthan,
S.I.Blaber,
M.J.Bernett,
I.A.Scarisbrick,
M.A.Juliano,
and
M.Blaber
(2005).
1.70 A X-ray structure of human apo kallikrein 1: structural changes upon peptide inhibitor/substrate binding.
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Proteins,
58,
802-814.
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PDB code:
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A.Bayés,
T.Tsetsenis,
S.Ventura,
J.Vendrell,
F.X.Aviles,
and
G.Sotiropoulou
(2004).
Human kallikrein 6 activity is regulated via an autoproteolytic mechanism of activation/inactivation.
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Biol Chem,
385,
517-524.
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C.A.Borgoño,
and
E.P.Diamandis
(2004).
The emerging roles of human tissue kallikreins in cancer.
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Nat Rev Cancer,
4,
876-890.
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C.Caubet,
N.Jonca,
M.Brattsand,
M.Guerrin,
D.Bernard,
R.Schmidt,
T.Egelrud,
M.Simon,
and
G.Serre
(2004).
Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.
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J Invest Dermatol,
122,
1235-1244.
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G.P.Christophi,
P.J.Isackson,
S.Blaber,
M.Blaber,
M.Rodriguez,
and
I.A.Scarisbrick
(2004).
Distinct promoters regulate tissue-specific and differential expression of kallikrein 6 in CNS demyelinating disease.
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J Neurochem,
91,
1439-1449.
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L.Y.Luo,
G.Yousef,
and
E.P.Diamandis
(2003).
Human tissue kallikreins and testicular cancer.
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APMIS,
111,
225.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
