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PDBsum entry 2p4e

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protein metals Protein-protein interface(s) links
Hydrolase PDB id
2p4e
Jmol
Contents
Protein chains
92 a.a. *
494 a.a. *
Metals
_HG ×2
Waters ×371
* Residue conservation analysis
PDB id:
2p4e
Name: Hydrolase
Title: Crystal structure of pcsk9
Structure: Proprotein convertase subtilisin/kexin type 9. Chain: p, a. Synonym: proprotein convertase pc9, subtilisin/kexin-like p pc9, neural apoptosis-regulated convertase 1, narc-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pcsk9, narc1. Expressed in: cricetulus griseus. Expression_system_taxid: 10029.
Resolution:
1.98Å     R-factor:   0.202     R-free:   0.250
Authors: D.Cunningham,D.E.Danley,F.K.Geoghegan,M.C.Griffor,J.L.Hawkin
Key ref:
D.Cunningham et al. (2007). Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Biol, 14, 413-419. PubMed id: 17435765 DOI: 10.1038/nsmb1235
Date:
12-Mar-07     Release date:   10-Apr-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q8NBP7  (PCSK9_HUMAN) -  Proprotein convertase subtilisin/kexin type 9
Seq:
Struc:
 
Seq:
Struc:
692 a.a.
92 a.a.
Protein chain
Pfam   ArchSchema ?
Q8NBP7  (PCSK9_HUMAN) -  Proprotein convertase subtilisin/kexin type 9
Seq:
Struc:
 
Seq:
Struc:
692 a.a.
494 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     serine-type endopeptidase activity     1 term  

 

 
DOI no: 10.1038/nsmb1235 Nat Struct Biol 14:413-419 (2007)
PubMed id: 17435765  
 
 
Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia.
D.Cunningham, D.E.Danley, K.F.Geoghegan, M.C.Griffor, J.L.Hawkins, T.A.Subashi, A.H.Varghese, M.J.Ammirati, J.S.Culp, L.R.Hoth, M.N.Mansour, K.M.McGrath, A.P.Seddon, S.Shenolikar, K.J.Stutzman-Engwall, L.C.Warren, D.Xia, X.Qiu.
 
  ABSTRACT  
 
Proprotein convertase subtilisin kexin type 9 (PCSK9) lowers the abundance of surface low-density lipoprotein (LDL) receptor through an undefined mechanism. The structure of human PCSK9 shows the subtilisin-like catalytic site blocked by the prodomain in a noncovalent complex and inaccessible to exogenous ligands, and that the C-terminal domain has a novel fold. Biosensor studies show that PCSK9 binds the extracellular domain of LDL receptor with K(d) = 170 nM at the neutral pH of plasma, but with a K(d) as low as 1 nM at the acidic pH of endosomes. The D374Y gain-of-function mutant, associated with hypercholesterolemia and early-onset cardiovascular disease, binds the receptor 25 times more tightly than wild-type PCSK9 at neutral pH and remains exclusively in a high-affinity complex at the acidic pH. PCSK9 may diminish LDL receptors by a mechanism that requires direct binding but not necessarily receptor proteolysis.
 
  Selected figure(s)  
 
Figure 2.
(a) Stereo view of C overlay of PCSK9 (green), PC1 (yellow) and subtilisin (magenta). (b) Structure near Trp72. Gray, C trace of prodomain; green and yellow, side chain carbons of pro- and catalytic domain residues, respectively. (c) Western blots showing effect of mutations on PCSK9 processing inside cells and secreted into media. WT, wild-type.
Figure 4.
(a) Ribbon diagram viewed along the three-fold axis. Each blade is shown in a different color; modules are labeled. Strand 4 of M2 is disordered in the structure. (b) Stereo view of overlaid C traces and disulfides (green) of modules (yellow, M1; cyan, M2; magenta, M3). (c) Ribbon diagram of M1, with N and C termini labeled. Green ball-and-stick models represent disulfides. (d) Stereo view of PCSK9 and furin with catalytic domains superimposed. Gray, furin; red, PCSK9 P' peptide; yellow, PCSK9 catalytic domain (ends at 449); cyan, PCSK9 C-terminal domain (starts at 453); magenta space-fill, Ser386. A few other PCSK9 residues are labeled.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2007, 14, 413-419) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19571328 G.Dubuc, M.Tremblay, G.Paré, H.Jacques, J.Hamelin, S.Benjannet, L.Boulet, J.Genest, L.Bernier, N.G.Seidah, and J.Davignon (2010).
A new method for measurement of total plasma PCSK9: clinical applications.
  J Lipid Res, 51, 140-149.  
19196236 C.J.Duff, M.J.Scott, I.T.Kirby, S.E.Hutchinson, S.L.Martin, and N.M.Hooper (2009).
Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor.
  Biochem J, 419, 577-584.  
19443683 J.C.Chan, D.E.Piper, Q.Cao, D.Liu, C.King, W.Wang, J.Tang, Q.Liu, J.Higbee, Z.Xia, Y.Di, S.Shetterly, Z.Arimura, H.Salomonis, W.G.Romanow, S.T.Thibault, R.Zhang, P.Cao, X.P.Yang, T.Yu, M.Lu, M.W.Retter, G.Kwon, K.Henne, O.Pan, M.M.Tsai, B.Fuchslocher, E.Yang, L.Zhou, K.J.Lee, M.Daris, J.Sheng, Y.Wang, W.D.Shen, W.C.Yeh, M.Emery, N.P.Walker, B.Shan, M.Schwarz, and S.M.Jackson (2009).
A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
  Proc Natl Acad Sci U S A, 106, 9820-9825.
PDB code: 3h42
  19020338 J.D.Horton, J.C.Cohen, and H.H.Hobbs (2009).
PCSK9: a convertase that coordinates LDL catabolism.
  J Lipid Res, 50, S172-S177.  
19191301 M.Abifadel, J.P.Rabès, M.Devillers, A.Munnich, D.Erlich, C.Junien, M.Varret, and C.Boileau (2009).
Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease.
  Hum Mutat, 30, 520-529.  
19224862 M.C.McNutt, H.J.Kwon, C.Chen, J.R.Chen, J.D.Horton, and T.A.Lagace (2009).
Antagonism of Secreted PCSK9 Increases Low Density Lipoprotein Receptor Expression in HepG2 Cells.
  J Biol Chem, 284, 10561-10570.
PDB codes: 3gcw 3gcx
19001363 M.J.Bottomley, A.Cirillo, L.Orsatti, L.Ruggeri, T.S.Fisher, J.C.Santoro, R.T.Cummings, R.M.Cubbon, P.Lo Surdo, A.Calzetta, A.Noto, J.Baysarowich, M.Mattu, F.Talamo, R.De Francesco, C.P.Sparrow, A.Sitlani, and A.Carfí (2009).
Structural and Biochemical Characterization of the Wild Type PCSK9-EGF(AB) Complex and Natural Familial Hypercholesterolemia Mutants.
  J Biol Chem, 284, 1313-1323.
PDB codes: 2w2m 2w2n 2w2o 2w2p 2w2q
19063703 N.G.Seidah (2009).
PCSK9 as a therapeutic target of dyslipidemia.
  Expert Opin Ther Targets, 13, 19-28.  
19635789 S.Poirier, G.Mayer, V.Poupon, P.S.McPherson, R.Desjardins, K.Ly, M.C.Asselin, R.Day, F.J.Duclos, M.Witmer, R.Parker, A.Prat, and N.G.Seidah (2009).
Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route.
  J Biol Chem, 284, 28856-28864.  
19060325 Y.Luo, L.Warren, D.Xia, H.Jensen, T.Sand, S.Petras, W.Qin, K.S.Miller, and J.Hawkins (2009).
Function and distribution of circulating human PCSK9 expressed extrahepatically in transgenic mice.
  J Lipid Res, 50, 1581-1588.  
18354138 A.Grefhorst, M.C.McNutt, T.A.Lagace, and J.D.Horton (2008).
Plasma PCSK9 preferentially reduces liver LDL receptors in mice.
  J Lipid Res, 49, 1303-1311.  
18666258 A.Zaid, A.Roubtsova, R.Essalmani, J.Marcinkiewicz, A.Chamberland, J.Hamelin, M.Tremblay, H.Jacques, W.Jin, J.Davignon, N.G.Seidah, and A.Prat (2008).
Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.
  Hepatology, 48, 646-654.  
18197702 D.Fan, P.G.Yancey, S.Qiu, L.Ding, E.J.Weeber, M.F.Linton, and S.Fazio (2008).
Self-association of human PCSK9 correlates with its LDLR-degrading activity.
  Biochemistry, 47, 1631-1639.  
18753623 D.W.Zhang, R.Garuti, W.J.Tang, J.C.Cohen, and H.H.Hobbs (2008).
Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor.
  Proc Natl Acad Sci U S A, 105, 13045-13050.  
18799458 G.Mayer, S.Poirier, and N.G.Seidah (2008).
Annexin A2 Is a C-terminal PCSK9-binding Protein That Regulates Endogenous Low Density Lipoprotein Receptor Levels.
  J Biol Chem, 283, 31791-31801.  
18250299 H.J.Kwon, T.A.Lagace, M.C.McNutt, J.D.Horton, and J.Deisenhofer (2008).
Molecular basis for LDL receptor recognition by PCSK9.
  Proc Natl Acad Sci U S A, 105, 1820-1825.
PDB code: 3bps
18266662 J.Cameron, O.L.Holla, J.K.Laerdahl, M.A.Kulseth, T.Ranheim, T.Rognes, K.E.Berge, and T.P.Leren (2008).
Characterization of novel mutations in the catalytic domain of the PCSK9 gene.
  J Intern Med, 263, 420-431.  
18631360 J.Cameron, ..L.Holla, K.E.Berge, M.A.Kulseth, T.Ranheim, T.P.Leren, and J.K.Laerdahl (2008).
Investigations on the evolutionary conservation of PCSK9 reveal a functionally important protrusion.
  FEBS J, 275, 4121-4133.  
18547436 J.Mayne, T.Dewpura, A.Raymond, M.Cousins, A.Chaplin, K.A.Lahey, S.A.Lahaye, M.Mbikay, T.C.Ooi, and M.Chrétien (2008).
Plasma PCSK9 levels are significantly modified by statins and fibrates in humans.
  Lipids Health Dis, 7, 22.  
18300938 K.Ding, and I.J.Kullo (2008).
Molecular population genetics of PCSK9: a signature of recent positive selection.
  Pharmacogenet Genomics, 18, 169-179.  
18672372 P.Costet, M.Krempf, and B.Cariou (2008).
PCSK9 and LDL cholesterol: unravelling the target to design the bullet.
  Trends Biochem Sci, 33, 426-434.  
18052825 R.J.Schmidt, Y.Zhang, Y.Zhao, Y.W.Qian, H.Wang, A.Lin, M.E.Ehsani, X.Yu, G.Wang, J.Singh, E.W.Su, S.Li, R.J.Konrad, and G.Cao (2008).
A novel splicing variant of proprotein convertase subtilisin/kexin type 9.
  DNA Cell Biol, 27, 183-189.  
18388699 S.Calandra, and P.Tarugi (2008).
Genetics and molecular biology: proprotein convertase subtilisin/kexin type 9 and LDL receptor--an intriguing story.
  Curr Opin Lipidol, 19, 208-211.  
18331356 S.D.Roosendaal, J.Kerver, M.Schipper, K.W.Rodenburg, and D.J.Van der Horst (2008).
The complex of the insect LDL receptor homolog, lipophorin receptor, LpR, and its lipoprotein ligand does not dissociate under endosomal conditions.
  FEBS J, 275, 1751-1766.  
18245819 S.Kourimate, C.Le May, C.Langhi, A.L.Jarnoux, K.Ouguerram, Y.Zaïr, P.Nguyen, M.Krempf, B.Cariou, and P.Costet (2008).
Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9.
  J Biol Chem, 283, 9666-9673.  
18039658 S.Poirier, G.Mayer, S.Benjannet, E.Bergeron, J.Marcinkiewicz, N.Nassoury, H.Mayer, J.Nimpf, A.Prat, and N.G.Seidah (2008).
The Proprotein Convertase PCSK9 Induces the Degradation of Low Density Lipoprotein Receptor (LDLR) and Its Closest Family Members VLDLR and ApoER2.
  J Biol Chem, 283, 2363-2372.  
18498363 T.Dewpura, A.Raymond, J.Hamelin, N.G.Seidah, M.Mbikay, M.Chrétien, and J.Mayne (2008).
PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans.
  FEBS J, 275, 3480-3493.  
17502100 D.E.Piper, S.Jackson, Q.Liu, W.G.Romanow, S.Shetterly, S.T.Thibault, B.Shan, and N.P.Walker (2007).
The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol.
  Structure, 15, 545-552.
PDB code: 2pmw
17804797 E.N.Hampton, M.W.Knuth, J.Li, J.L.Harris, S.A.Lesley, and G.Spraggon (2007).
The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain.
  Proc Natl Acad Sci U S A, 104, 14604-14609.
PDB code: 2qtw
17537735 M.C.McNutt, T.A.Lagace, and J.D.Horton (2007).
Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells.
  J Biol Chem, 282, 20799-20803.  
17870468 S.C.Blacklow (2007).
Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers.
  Curr Opin Struct Biol, 17, 419-426.  
17493938 T.S.Fisher, P.Lo Surdo, S.Pandit, M.Mattu, J.C.Santoro, D.Wisniewski, R.T.Cummings, A.Calzetta, R.M.Cubbon, P.A.Fischer, A.Tarachandani, R.De Francesco, S.D.Wright, C.P.Sparrow, A.Carfi, and A.Sitlani (2007).
Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation.
  J Biol Chem, 282, 20502-20512.  
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.