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5z5o

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Revision as of 07:06, 12 December 2018

Structure of Pycnonodysostosis disease related I249T mutant of human cathepsin K

Structural highlights

5z5o is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , ,
NonStd Res:
Related:	1by8
Gene:	CTSK, CTSO, CTSO2 (HUMAN)
Activity:	Cathepsin K, with EC number 3.4.22.38
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CATK_HUMAN] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:265800]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.^[1] ^[2] ^[3] ^[4]

Function

[CATK_HUMAN] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation.

Publication Abstract from PubMed

Human cathepsin K (CTSK) is a collagenolytic lysosomal cysteine protease that plays an important role in bone turnover. Mutation in CTSK gene is associated with loss of collagenolytic activity of CTSK leading to an autosomal recessive bone disorder called pycnodysostosis. Though a number of pycnodysostotic missense mutations have been reported, underlying mechanism of the disease is not clear. In this study we investigated in vitro six recombinant pycnodysostosis related mutants of human CTSK (G79E, I249T, G243E, G303E, G319C and Q187P). While all the mutants, like wild-type, show similar high level of expression in E. coli, four of them (G79E, G303E, G319C and Q187P) are inactive, unstable and spontaneously degrade during purification process. In contrast, proteolytic/collagenolytic activity, zymogen activation kinetics and stability of G243E and I249T mutants are nominally affected. Crystal structure of I249T at 1.92A resolution shows that the mutation in R-domain causes conformational changes of a surface loop in L-domain though the catalytic cleft remains unaltered. Molecular simulation, normal mode analysis and Fluorescence life time measurement eliminated the possibility that the change in L-domain surface loop orientation is a crystallization artefact. CD-based thermal melting profile indicates that stability of I249T is significantly higher than wild-type. Our studies first time reports that pycnodysostosis are not always correlated with either a complete loss of proteolytic activity or at least collagenolytic activity due to mutation of CTSK gene. The first crystal structure of a pycnodysostotic mutant (I249T) provides critical information that may pave new avenues towards understanding the disease at molecular level. This article is protected by copyright. All rights reserved.

Not all pycnodysostosis-related mutants of human cathepsin K are inactive: Crystal structure and biochemical studies of an active mutant I249T.,Roy S, Das Chakraborty S, Biswas S FEBS J. 2018 Sep 10. doi: 10.1111/febs.14655. PMID:30199612^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996 Aug 30;273(5279):1236-8. PMID:8703060
↑ Gelb BD, Willner JP, Dunn TM, Kardon NB, Verloes A, Poncin J, Desnick RJ. Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. Am J Hum Genet. 1998 Apr;62(4):848-54. PMID:9529353 doi:S0002-9297(07)60977-X
↑ Ho N, Punturieri A, Wilkin D, Szabo J, Johnson M, Whaley J, Davis J, Clark A, Weiss S, Francomano C. Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein. J Bone Miner Res. 1999 Oct;14(10):1649-53. PMID:10491211
↑ Haagerup A, Hertz JM, Christensen MF, Binderup H, Kruse TA. Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. Eur J Hum Genet. 2000 Jun;8(6):431-6. PMID:10878663 doi:10.1038/sj.ejhg.5200481
↑ Roy S, Das Chakraborty S, Biswas S. Not all pycnodysostosis-related mutants of human cathepsin K are inactive: Crystal structure and biochemical studies of an active mutant I249T. FEBS J. 2018 Sep 10. doi: 10.1111/febs.14655. PMID:30199612 doi:http://dx.doi.org/10.1111/febs.14655

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5z5o"

@@ Line 3: / Line 3: @@
 <StructureSection load='5z5o' size='340' side='right' caption='[[5z5o]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5z5o]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Z5O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Z5O FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5z5o]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Z5O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Z5O FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEB:O-BENZYLSULFONYL-SERINE'>SEB</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1by8|1by8]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTSK, CTSO, CTSO2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cathepsin_K Cathepsin K], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.38 3.4.22.38] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5z5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5z5o OCA], [http://pdbe.org/5z5o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5z5o RCSB], [http://www.ebi.ac.uk/pdbsum/5z5o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5z5o ProSAT]</span></td></tr>
@@ Line 28: / Line 29: @@
 </StructureSection>
 [[Category: Cathepsin K]]
+[[Category: Human]]
 [[Category: Biswas, S]]
 [[Category: Roy, S]]

5z5o

From Proteopedia

Revision as of 07:06, 12 December 2018

Structure of Pycnonodysostosis disease related I249T mutant of human cathepsin K

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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