spacer
spacer

PDBsum entry 1n9j

Go to PDB code: 
protein Protein-protein interface(s) links
Hydrolase inhibitor PDB id
1n9j
Jmol
Contents
Protein chain
98 a.a. *
* Residue conservation analysis
PDB id:
1n9j
Name: Hydrolase inhibitor
Title: Solution structure of the 3d domain swapped dimer of stefin a
Structure: Cystatin a. Chain: a, b. Synonym: stefin a, cystatin as. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
NMR struc: 1 models
Authors: R.A.Staniforth,S.Giannini,L.D.Higgins,M.J.Conroy, A.M.Hounslow,R.Jerala,C.J.Craven,J.P.Waltho
Key ref:
R.A.Staniforth et al. (2001). Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily. EMBO J, 20, 4774-4781. PubMed id: 11532941 DOI: 10.1093/emboj/20.17.4774
Date:
25-Nov-02     Release date:   25-Feb-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01040  (CYTA_HUMAN) -  Cystatin-A
Seq:
Struc:
98 a.a.
98 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   6 terms 
  Biological process     cell adhesion   7 terms 
  Biochemical function     structural molecule activity     6 terms  

 

 
DOI no: 10.1093/emboj/20.17.4774 EMBO J 20:4774-4781 (2001)
PubMed id: 11532941  
 
 
Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily.
R.A.Staniforth, S.Giannini, L.D.Higgins, M.J.Conroy, A.M.Hounslow, R.Jerala, C.J.Craven, J.P.Waltho.
 
  ABSTRACT  
 
Cystatins, an amyloid-forming structural superfamily, form highly stable, domain-swapped dimers at physiological protein concentrations. In chicken cystatin, the active monomer is a kinetic trap en route to dimerization, and any changes in solution conditions or mutations that destabilize the folded state shorten the lifetime of the monomeric form. In such circumstances, amyloidogenesis will start from conditions where a domain-swapped dimer is the most prevalent species. Domain swapping occurs by a rearrangement of loop I, generating the new intermonomer interface between strands 2 and 3. The transition state for dimerization has a high level of hydrophobic group exposure, indicating that gross conformational perturbation is required for domain swapping to occur. Dimerization also occurs when chicken cystatin is in its reduced, molten-globule state, implying that the organization of secondary structure in this state mirrors that in the folded state and that domain swapping is not limited to the folded states of proteins. Although the interface between cystatin-fold units is poorly defined for cystatin A, the dimers are the appropriate size to account for the electron-dense regions in amyloid protofilaments.
 
  Selected figure(s)  
 
Figure 4.
Figure 4 (A) Amide -amide region from a 100 ms isotope-filtered NOESY experiment (Otting et al., 1986) on an hCA dimer made from a 1:1 mixture of uniformly 15N-labelled and unlabelled monomers, showing the sum of the signal from components where the filters are on -off and where they are off -on. Thus, only intermolecular d[NN] NOEs are observed in this region of the spectrum. The labelled cross-peaks are cross-strand NOEs between strand 2 and strand 3. (B) Section from a 100 ms NOESY experiment on a cC dimer made from a 1:1 mixture of uniformly 13C,15N-labelled and unlabelled monomers. Illustrated are two intermolecular NOE cross-peaks from the side chain of F27 to that of I107. Components of the cross-peaks where magnetization has been transferred from H(13C) to H(12C) and vice versa flank the central H(12C) to H(12C) component. (C) A schematic representation of (B), showing the expected peak pattern at the S/N ratio recorded in (B). The circle and square symbols represent the cross-peaks of F27h and F27h , respectively. The unfilled symbols represent components that are unresolvable from more intense signals.
Figure 5.
Figure 5 (A) Ensemble of the eight lowest energy structures of the domain-swapped hCA dimer. The well-defined regions (T13 -Q46, N52 -P74 and L80 -F98) of a cystatin-fold unit overlay with an r.m.s.d. to the mean structure of 0.50 and 1.02 for the backbone and heavy atoms, respectively. (B) Ribbon representation of the minimized averaged dimer structure of hCA, created using the programs MOLSCRIPT (Kraulis, 1991) and Raster3D (Merritt and Murphy, 1994). The component monomers are coloured blue and red. The closed interface is formed between strands 2 and 3. Loop I in the monomer merges these elements into a continuous strand in the dimer. The secondary structure elements comprise 1, G5 -P11; , E15 -T31; 2/3, Q42 -A59; 4, K63 -S72; and 5, V81 -K89. (C) Schematic representation of a possible longitudinal assembly of cystatin dimers into a continuous -sheet structure where dimers are connected via an interface between strands 1 and 5. Such an assembly has the potential to be favoured energetically and kinetically in comparison with the equivalent association of monomers due to the increased effective concentration of monomers in the dimer. (D) A space-filling model illustrating how four cystatin-fold units, made up of two domain-swapped dimers of the type shown in (B), can be fitted into the cross-section of a generic fibril. In this model, the fibril would be formed by the assembly of further domain-swapped dimers onto each of the visible dimers in the manner illustrated in (C).
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2001, 20, 4774-4781) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21539796 C.Jelinska, P.J.Davis, M.Kenig, E.Zerovnik, S.J.Kokalj, G.Gunčar, D.Turk, V.Turk, D.T.Clarke, J.P.Waltho, and R.A.Staniforth (2011).
Modulation of contact order effects in the two-state folding of stefins a and B.
  Biophys J, 100, 2268-2274.  
21086533 A.Taler-Verčič, and E.Zerovnik (2010).
Binding of amyloid peptides to domain-swapped dimers of other amyloid-forming proteins may prevent their neurotoxicity.
  Bioessays, 32, 1020-1024.  
20976204 C.H.Chu, W.C.Lo, H.W.Wang, Y.C.Hsu, J.K.Hwang, P.C.Lyu, T.W.Pai, and C.Y.Tang (2010).
Detection and alignment of 3D domain swapping proteins using angle-distance image-based secondary structural matching techniques.
  PLoS One, 5, e13361.  
  20173285 J.Ochieng, and G.Chaudhuri (2010).
Cystatin superfamily.
  J Health Care Poor Underserved, 21, 51-70.  
19955183 K.Skerget, A.Taler-Vercic, A.Bavdek, V.Hodnik, S.Ceru, M.Tusek-Znidaric, T.Kumm, D.Pitsi, M.Pompe-Novak, P.Palumaa, S.Soriano, N.Kopitar-Jerala, V.Turk, G.Anderluh, and E.Zerovnik (2010).
Interaction between oligomers of stefin B and amyloid-beta in vitro and in cells.
  J Biol Chem, 285, 3201-3210.  
20545851 M.Kotsyfakis, H.Horka, J.Salat, and J.F.Andersen (2010).
The crystal structures of two salivary cystatins from the tick Ixodes scapularis and the effect of these inhibitors on the establishment of Borrelia burgdorferi infection in a murine model.
  Mol Microbiol, 77, 456-470.
PDB codes: 3lh4 3li7 3mwz
20078424 S.Ceru, R.Layfield, T.Zavasnik-Bergant, U.Repnik, N.Kopitar-Jerala, V.Turk, and E.Zerovnik (2010).
Intracellular aggregation of human stefin B: confocal and electron microscopy study.
  Biol Cell, 102, 319-334.  
18636508 K.Skerget, A.Vilfan, M.Pompe-Novak, V.Turk, J.P.Waltho, D.Turk, and E.Zerovnik (2009).
The mechanism of amyloid-fibril formation by stefin B: temperature and protein concentration dependence of the rates.
  Proteins, 74, 425-436.  
19137579 S.Rodziewicz-Motowidło, J.Iwaszkiewicz, R.Sosnowska, P.Czaplewska, E.Sobolewski, A.Szymańska, K.Stachowiak, and A.Liwo (2009).
The role of the Val57 amino-acid residue in the hinge loop of the human cystatin C. Conformational studies of the beta2-L1-beta3 segments of wild-type human cystatin C and its mutants.
  Biopolymers, 91, 373-383.  
18620534 A.Shukla, M.Raje, and P.Guptasarma (2008).
Coalescence of spherical beads of retro-HSP12.6 into linear and ring-shaped amyloid nanofibers.
  Biochemistry (Mosc), 73, 681-685.  
18036195 C.Fasano, V.Campana, B.Griffiths, G.Kelly, G.Schiavo, and C.Zurzolo (2008).
Gene expression profile of quinacrine-cured prion-infected mouse neuronal cells.
  J Neurochem, 105, 239-250.  
  19158505 R.N.Rambaran, and L.C.Serpell (2008).
Amyloid fibrils: abnormal protein assembly.
  Prion, 2, 112-117.  
18925453 S.Ceru, S.J.Kokalj, S.Rabzelj, M.Skarabot, I.Gutierrez-Aguirre, N.Kopitar-Jerala, G.Anderluh, D.Turk, V.Turk, and E.Zerovnik (2008).
Size and morphology of toxic oligomers of amyloidogenic proteins: a case study of human stefin B.
  Amyloid, 15, 147-159.  
17882537 S.Sharma, and P.Guptasarma (2008).
Evidence of Native-like Substructure(s) in Polypeptide Chains of Carbonic Anhydrase Deposited into Insoluble Aggregates During Thermal Unfolding.
  Protein J, 27, 50-58.  
17588526 T.R.Jahn, and S.E.Radford (2008).
Folding versus aggregation: polypeptide conformations on competing pathways.
  Arch Biochem Biophys, 469, 100-117.  
17701471 E.Zerovnik, M.Skarabot, K.Skerget, S.Giannini, V.Stoka, S.Jenko-Kokalj, and R.A.Staniforth (2007).
Amyloid fibril formation by human stefin B: influence of pH and TFE on fibril growth and morphology.
  Amyloid, 14, 237-247.  
17855342 H.H.von Horsten, S.S.Johnson, S.K.SanFrancisco, M.C.Hastert, S.M.Whelly, and G.A.Cornwall (2007).
Oligomerization and transglutaminase cross-linking of the cystatin CRES in the mouse epididymal lumen: potential mechanism of extracellular quality control.
  J Biol Chem, 282, 32912-32923.  
16981672 D.Eisenberg, R.Nelson, M.R.Sawaya, M.Balbirnie, S.Sambashivan, M.I.Ivanova, A...Madsen, and C.Riekel (2006).
The structural biology of protein aggregation diseases: Fundamental questions and some answers.
  Acc Chem Res, 39, 568-575.  
16939620 E.Zerovnik, K.Skerget, M.Tusek-Znidaric, C.Loeschner, M.W.Brazier, and D.R.Brown (2006).
High affinity copper binding by stefin B (cystatin B) and its role in the inhibition of amyloid fibrillation.
  FEBS J, 273, 4250-4263.  
16407060 F.Ding, K.C.Prutzman, S.L.Campbell, and N.V.Dokholyan (2006).
Topological determinants of protein domain swapping.
  Structure, 14, 5.  
16434741 J.He, Y.Song, N.Ueyama, A.Saito, H.Azakami, and A.Kato (2006).
Prevention of amyloid fibril formation of amyloidogenic chicken cystatin by site-specific glycosylation in yeast.
  Protein Sci, 15, 213-222.  
16342276 M.Kenig, S.Jenko-Kokalj, M.Tusek-Znidaric, M.Pompe-Novak, G.Guncar, D.Turk, J.P.Waltho, R.A.Staniforth, F.Avbelj, and E.Zerovnik (2006).
Folding and amyloid-fibril formation for a series of human stefins' chimeras: any correlation?
  Proteins, 62, 918-927.  
16963458 M.R.Ho, Y.C.Lou, W.C.Lin, P.C.Lyu, W.N.Huang, and C.Chen (2006).
Human pancreatitis-associated protein forms fibrillar aggregates with a native-like conformation.
  J Biol Chem, 281, 33566-33576.
PDB code: 2go0
16519682 M.Rodríguez, A.Benito, M.Ribó, and M.Vilanova (2006).
Characterization of the dimerization process of a domain-swapped dimeric variant of human pancreatic ribonuclease.
  FEBS J, 273, 1166-1176.  
16563741 R.Nelson, and D.Eisenberg (2006).
Recent atomic models of amyloid fibril structure.
  Curr Opin Struct Biol, 16, 260-265.  
16415060 Y.B.Yan, J.Zhang, H.W.He, and H.M.Zhou (2006).
Oligomerization and aggregation of bovine pancreatic ribonuclease A: characteristic events observed by FTIR spectroscopy.
  Biophys J, 90, 2525-2533.  
16698921 Z.Guo, and D.Eisenberg (2006).
Runaway domain swapping in amyloid-like fibrils of T7 endonuclease I.
  Proc Natl Acad Sci U S A, 103, 8042-8047.  
15596505 A.Merlino, M.A.Ceruso, L.Vitagliano, and L.Mazzarella (2005).
Open interface and large quaternary structure movements in 3D domain swapped proteins: insights from molecular dynamics simulations of the C-terminal swapped dimer of ribonuclease A.
  Biophys J, 88, 2003-2012.  
16170782 R.Janowski, M.Kozak, M.Abrahamson, A.Grubb, and M.Jaskolski (2005).
3D domain-swapped human cystatin C with amyloidlike intermolecular beta-sheets.
  Proteins, 61, 570-578.
PDB code: 1tij
16155205 S.Rabzelj, V.Turk, and E.Zerovnik (2005).
In vitro study of stability and amyloid-fibril formation of two mutants of human stefin B (cystatin B) occurring in patients with EPM1.
  Protein Sci, 14, 2713-2722.  
16148936 S.Sambashivan, Y.Liu, M.R.Sawaya, M.Gingery, and D.Eisenberg (2005).
Amyloid-like fibrils of ribonuclease A with three-dimensional domain-swapped and native-like structure.
  Nature, 437, 266-269.
PDB codes: 2apq 2apu
16080717 Y.C.Su, J.C.Lin, and H.L.Liu (2005).
Homology model and molecular dynamics simulation of carp ovum cystatin.
  Biotechnol Prog, 21, 1315-1320.  
14747998 B.Japelj, J.P.Waltho, and R.Jerala (2004).
Comparison of backbone dynamics of monomeric and domain-swapped stefin A.
  Proteins, 54, 500-512.  
14724277 G.Plakoutsi, N.Taddei, M.Stefani, and F.Chiti (2004).
Aggregation of the Acylphosphatase from Sulfolobus solfataricus: the folded and partially unfolded states can both be precursors for amyloid formation.
  J Biol Chem, 279, 14111-14119.  
14691222 M.Kenig, S.Berbić, A.Krijestorac, L.Kroon-Zitko, M.Tusek, M.Pompe-Novak, and E.Zerovnik (2004).
Differences in aggregation properties of three site-specific mutants of recombinant human stefin B.
  Protein Sci, 13, 63-70.  
15102455 R.Tycko (2004).
Progress towards a molecular-level structural understanding of amyloid fibrils.
  Curr Opin Struct Biol, 14, 96.  
15048832 S.Jenko, M.Skarabot, M.Kenig, G.Guncar, I.Musevic, D.Turk, and E.Zerovnik (2004).
Different propensity to form amyloid fibrils by two homologous proteins-Human stefins A and B: searching for an explanation.
  Proteins, 55, 417-425.  
15452225 W.Xiang, O.Windl, G.Wünsch, M.Dugas, A.Kohlmann, N.Dierkes, I.M.Westner, and H.A.Kretzschmar (2004).
Identification of differentially expressed genes in scrapie-infected mouse brains by using global gene expression technology.
  J Virol, 78, 11051-11060.  
12525699 C.A.Baker, and L.Manuelidis (2003).
Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease.
  Proc Natl Acad Sci U S A, 100, 675-679.  
12623012 F.Rousseau, J.W.Schymkowitz, and L.S.Itzhaki (2003).
The unfolding story of three-dimensional domain swapping.
  Structure, 11, 243-251.  
12833549 F.Sica, A.Di Fiore, A.Zagari, and L.Mazzarella (2003).
The unswapped chain of bovine seminal ribonuclease: Crystal structure of the free and liganded monomeric derivative.
  Proteins, 52, 263-271.
PDB codes: 1n1x 1n3z
12787072 G.Vattemi, W.K.Engel, J.McFerrin, and V.Askanas (2003).
Cystatin C colocalizes with amyloid-beta and coimmunoprecipitates with amyloid-beta precursor protein in sporadic inclusion-body myositis muscles.
  J Neurochem, 85, 1539-1546.  
12777380 N.Fay, Y.Inoue, L.Bousset, H.Taguchi, and R.Melki (2003).
Assembly of the yeast prion Ure2p into protein fibrils. Thermodynamic and kinetic characterization.
  J Biol Chem, 278, 30199-30205.  
14627730 T.Scheuermann, B.Schulz, A.Blume, E.Wahle, R.Rudolph, and E.Schwarz (2003).
Trinucleotide expansions leading to an extended poly-L-alanine segment in the poly (A) binding protein PABPN1 cause fibril formation.
  Protein Sci, 12, 2685-2692.  
12360234 D.A.Lomas, and R.W.Carrell (2002).
Serpinopathies and the conformational dementias.
  Nat Rev Genet, 3, 759-768.  
12135474 E.Zerovnik (2002).
Amyloid-fibril formation. Proposed mechanisms and relevance to conformational disease.
  Eur J Biochem, 269, 3362-3371.  
12108553 E.Zerovnik, V.Zavasnik-Bergant, N.Kopitar-Jerala, M.Pompe-Novak, M.Skarabot, K.Goldie, M.Ravnikar, I.Musevic, and V.Turk (2002).
Amyloid fibril formation by human stefin B in vitro: immunogold labelling and comparison to stefin A.
  Biol Chem, 383, 859-863.  
11839489 M.E.Newcomer (2002).
Protein folding and three-dimensional domain swapping: a strained relationship?
  Curr Opin Struct Biol, 12, 48-53.  
12021428 Y.Liu, and D.Eisenberg (2002).
3D domain swapping: as domains continue to swap.
  Protein Sci, 11, 1285-1299.  
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 codes are shown on the right.