- Email: [email protected]
A unifying hypothesis for explaining the mechanism of amyloid formation under conditions of increased oxidative stress
Bioscience Hypotheses (2008) 1, 209e212
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/bihy
A unifying hypothesis for explaining the mechanism of amyloid formation under conditions of increased oxidative stress Ayse Aslihan Aydemir-Koksoy* Department of Biophysics, School of Medicine, Ankara University, Sihhiye, 06100 Ankara, Turkey Received 25 July 2008; accepted 29 July 2008
KEYWORDS Cystatin c; Amyloid; Oxidative stres; Matrix metalloproteinases; Diabetes
Abstract Amyloid related organ dysfunction is a common feature of conditions associated with chronic oxidative injury such as diabetes, inflammation, neurodegenerative disorders, renal failure, and natural aging. Matrix metalloproteinases (MMPs) are a family of calcium and zinc-dependent endopeptidases comprised of 23 enzymes in the human. Among these, MMPs 2 and 9 are known as secretable forms, present in all body fluids and susceptible to activation by oxidants. Although MMPs are generally accepted and named for their effect on extracellular matrix turnover, their non-extracellular-matrix targets have emerged recently. Cystatin C (CysC) is a very potent inhibitor of cysteine proteinases, present in all body fluids. Its solubility is determined by its N-terminal sequence. CysC is known to polimerize and form fibrils and has been isolated from amyloids. The CysC isolated from amyloids is in the Nterminal truncated form. My hypothesis regarding amyloid formation is that CysC could be a substrate for MMPs 2 and 9, which upon cleaving the N-terminal off the CysC protein will render it insoluble and promote amyloid formation. Several in vitro studies have demonstrated degradation of CysC by MMPs. The implications of such a degradation in kidney glomerules (where the clearance of CysC occurs) could be of importance for understanding the mechanism of kidney failure e.g. in diabetes. This proposed mechanism for amyloid formation through degradation of CysC by MMPs, can be proposed for all cases of CysC related amyloid formation, such as those seen in cerebrovascular, cardiac and rheumatoid disorders. ª 2008 Elsevier Ltd. All rights reserved.
Introduction Chronic oxidative stress promotes amyloid formation [1e3]. Examples of amyloid related pathologies include type 2
* Tel.: þ90 312 310 3010x214; fax: þ90 312 310 6370. E-mail address: [email protected]
diabetes, Alzheimer’s disease, and senile cardiac amyloidosis [1,2,4]. In amyloid formation, the aggregate is formed by a change in the secondary-structure of the protein by formation of b-pleated-sheet, resulting in a less soluble conformation of the protein [3]. Cystatin C (CysC) belongs to the type 2 cystatin family of protease inhibitors. It is the dominating extracellular cysteine protease inhibitor of mammalians, produced at
1756-2392/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2008.07.005
210
A.A. Aydemir-Koksoy
a constant rate by the cells [5], with especially high concentrations in cerebrospinal fluid and synovial fluid [6]. The mature form of this secretable protein is 120 amino acids long, 13 kDa in size and its serum concentration is determined by glomerular filtration [5,7,8]. Enzyme binding by CysC requires an intact N-terminal and two beta hairpin loops [9]. Expression of a CysC variant, the L68Q, causes a disease named hereditary amyloid angiopathy leading to brain hemorrhage and death in early adulthood [10e12]. This variant of CysC is less stable than the wild-type and is susceptible to oligomerization and aggregation in vivo at body temperature through a mechanism called domain swapping [13e16]. Wild-type CysC can also give rise to amyloid formation over a very long time period as has been demonstrated for amyloid angiopathy of the elderly [17]. Human CysC isolated from the amyloid deposits is an Nterminal truncated from of the protein, 10 amino acids shorter than its original lengh [9,11,18]. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases which have a wide array of target proteins ranging from muscle myosin to serpins, along with extracellular matrix proteins [19,20]. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are known for functioning both intra- and extracellularly and have been reported to participate in the development of atherosclerosis, nephropathy and cardiomyopathy [21e25]. Both are produced as proenzymes and are activated by the ‘‘cysteine-switch’’ mechanism, which involves the cleavage of the N-terminal inhibitory peptide domain that results in dissociation of the cysteinyl sulphydryl and catalytic Znþ2 [26,27]. Other activation mechanisms which do not require the N-terminal cleavage of MMPs involve the oxidative modification of the cysteine thiol group within the propeptide domain [28,29]. A few papers and our unpublished observations have shown that under in vitro conditions CysC is a substrate for both MMP-2 and -9 [30,31].
Hypothesis In the light of the information given above I hypothesized that the activation of MMP-9 causes cleavage of N-terminal 11 aa residue from CysC which renders the protein to become insoluble and results in amyloid formation. Implications of this hypothesis brings explanation for the increased incidence amyloid formation in Alzheimer’s disease, pancreatic amyloidosis and nephropathy associated with diabetes.
Figure 1
Evaluation of the hypothesis in light of data from current literature CysC is the dominant inhibitor of cysteine proteases, especially cathepsin B, in the extracellular milieu [7,32]. The active form of CysC is a monomer of 120 amino acids long and forms 1:1 complexes with its target enzymes through the cysteine peptidase binding region which consists of N-terminal 2 b-hairpin loops [33,34]. This region contains the evolutionarily conserved Gly-11, Val-10, Lue-9 and Arg-8 residues which provide protein the ability to recognize and bind its targets with high affinity and specificity [35,36]. MMPs 2 and 9 are ubiquotosly expressed in human tissues and extracellular milieu. Data reported recently by Abdul-Hussien et al. [30], Overall and Dean [31] and my unpublished observations suggest that both MMP-2 and -9 degrade CysC in vitro. The analysis using LALIGN tool and the known cleavage sequences for MMP-2 and -9 from previously reported target proteins [20,37,38] gave me one sequence 70% homologous to MMP-9 cleavage sequences (Fig. 1). This putative cleavage site is within the first 12 residues of the N-terminal and the scissile bond is predicted to be between Arg-8 and Leu-9 (KPPR-LVGG). Analyzing for this cleavage site could be easily done in a lab with access to Edman degradation or mass spectrometry based protein sequence analyzers. A possible cleavage at this location could be enough to reduce the affinity of the protein for cathepsin B by 4000 fold as reported previously by Hall et al. [33]. This cleavage could also cause domain swapping between the N-terminal truncated cystatins, which will result in amyloid formation [39]. CysC amyloids isolated from patients with neurodegenerative diseases typically show the N-terminal truncation of the first 10 residues [18]. Current literature supports the co-localization of truncated CysC and increased MMP-9 expression. For example, presence of truncated CysC in urine samples isolated from patients with nephropathy was shown [40]. The increased expression of MMP-9 diabetic nephropathy has also been reported [41,42]. Truncated CysC and increased MMP-9 presence in cerebrospinal fluid are also reported for neurodegenerative disorders [43,44]. In this regard, should this hypothesis be correct, it could be suggested that therapies targeting control of MMP-9 activation, either directly (such as by doxycycline administration) or through reducing oxidative stress will be of therapeautic value for preventing amyloid formation.
MMP-9 cleavage motif for human CysC (X represents any amino acid and Xhy is a hydrophobic amino acid).
A unifying hypothesis for explaining the mechanism of amyloid formation
Conflict of interest The author has no conflict of interest.
Acknowledgements This study is granted by Ankara University Scientific Research Project BAP2003.08.09.120 and TUBA-GEBIP programme to reward successful young scientists.
References [1] Marzban L, Park K, Verchere CB. Islet amyloid polypeptide and type 2 diabetes. Exp Gerontol 2003;38:347e51. [2] Mancuso C, Scapagini G, Curro D, Giuffrida Stella AM, De Marco C, Butterfield DA, et al. Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front Biosci 2007;12:1107e23. [3] Monsellier E, Chiti F. Prevention of amyloid-like aggregation as a driving force of protein evolution. EMBO Rep 2007;8:737e42. [4] Dobson CM. Experimental investigation of protein folding and misfolding. Methods 2004;34:4e14. [5] Abrahamson M, Olafsson I, Palsdottir A, Ulvsback M, Lundwall A, Jensson O, et al. Structure and expression of the human cystatin C gene. Biochem J 1990;268:287e94. [6] Abrahamson M, Barrett AJ, Salvesen G, Grubb A. Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids. J Biol Chem 1986;261:11282e9. [7] Mussap M, Plebani M. Biochemistry and clinical role of human cystatin C. Crit Rev Clin Lab Sci 2004;41:467e550. [8] Tenstad O, Roald AB, Grubb A, Aukland K. Renal handling of radiolabelled human cystatin C in the rat. Scand J Clin Lab Invest 1996;56:409e14. [9] Janowski R, Abrahamson M, Grubb A, Jaskolski M. Domain swapping in N-truncated human cystatin C. J Mol Biol 2004; 341:151e60. [10] Olafsson I, Grubb A. Hereditary cystatin C amyloid angiopathy. Amyloid 2000;7:70e9. [11] Ghiso J, Jensson O, Frangione B. Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). Proc Natl Acad Sci U S A 1986;83:2974e8. [12] Jensson O, Palsdottir A, Thorsteinsson L, Arnason A, Abrahamson M, Olafsson I, et al. Cystatin C mutation causing amyloid angiopathy and brain hemorrhage. Biol Chem Hoppe Seyler 1990;371(Suppl):229e32. [13] Jaskolski M. 3D domain swapping, protein oligomerization, and amyloid formation. Acta Biochim Pol 2001;48:807e27. [14] Janowski R, Kozak M, Jankowska E, Grzonka Z, Grubb A, Abrahamson M, et al. Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. Nat Struct Biol 2001;8:316e20. [15] Nilsson M, Wang X, Rodziewicz-Motowidlo S, Janowski R, Lindstrom V, Onnerfjord P, et al. Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C: use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C. J Biol Chem 2004;279:24236e45. [16] Wahlbom M, Wang X, Lindstrom V, Carlemalm E, Jaskolski M, Grubb A. Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping. J Biol Chem 2007; 282:18318e26. [17] Yamada M. Cerebral amyloid angiopathy: an overview. Neuropathology 2000;20:8e22.
211
[18] Olafsson I, Gudmundsson G, Abrahamson M, Jensson O, Grubb A. The amino terminal portion of cerebrospinal fluid cystatin C in hereditary cystatin C amyloid angiopathy is not truncated: direct sequence analysis from agarose gel electropherograms. Scand J Clin Lab Invest 1990;50:85e93. [19] Chen EI, Li W, Godzik A, Howard EW, Smith JW. A residue in the S2 subsite controls substrate selectivity of matrix metalloproteinase-2 and matrix metalloproteinase-9. J Biol Chem 2003;278:17158e63. [20] Chen EI, Kridel SJ, Howard EW, Li W, Godzik A, Smith JW. A unique substrate recognition profile for matrix metalloproteinase-2. J Biol Chem 2002;277:4485e91. [21] Catania JM, Chen G, Parrish AR. Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol Renal Physiol 2007;292:F905e11. [22] Schulz R. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol 2007;47:211e42. [23] Thrailkill KM, Bunn RC, Moreau CS, Cockrell GE, Simpson PM, Coleman HN, et al. Matrix metalloproteinase-2 dysregulation in type 1 diabetes. Diabetes Care 2007;30:2321e6. [24] Sanders JS, Huitema MG, Hanemaaijer R, van Goor H, Kallenberg CG, Stegeman CA. Urinary matrix metalloproteinases reflect renal damage in anti-neutrophil cytoplasm autoantibody-associated vasculitis. Am J Physiol Renal Physiol 2007;293:F1927e34. [25] Rysz J, Banach M, Stolarek RA, Pasnik J, Cialkowska-Rysz A, Koktysz R, et al. Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy. J Nephrol 2007;20:444e52. [26] Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 1990;87:5578e82. [27] Fridman R, Toth M, Pena D, Mobashery S. Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res 1995;55:2548e55. [28] Okamoto T, Akaike T, Sawa T, Miyamoto Y, van der Vliet A, Maeda H. Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem 2001;276:29596e602. [29] Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, et al. Snitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 2002;297:1186e90. [30] Abdul-Hussien H, Soekhoe RG, Weber E, von der Thusen JH, Kleemann R, Mulder A, et al. Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases. Am J Pathol 2007;170:809e17. [31] Overall CM, Dean RA. Degradomics: systems biology of the protease web. Pleiotropic roles of MMPs in cancer. Cancer Metastasis Rev 2006;25:69e75. [32] Turk V, Bode W. The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett 1991;285:213e9. [33] Hall A, Hakansson K, Mason RW, Grubb A, Abrahamson M. Structural basis for the biological specificity of cystatin C. Identification of leucine 9 in the N-terminal binding region as a selectivity-conferring residue in the inhibition of mammalian cysteine peptidases. J Biol Chem 1995;270:5115e21. [34] Abrahamson M, Alvarez-Fernandez M, Nathanson CM. Cystatins. Biochem Soc Symp 2003:179e99. [35] Abrahamson M, Buttle DJ, Mason RW, Hansson H, Grubb A, Lilja H, et al. Regulation of cystatin C activity by serine proteinases. Biomed Biochim Acta 1991;50:587e93. [36] Bode W, Engh R, Musil D, Thiele U, Huber R, Karshikov A, et al. The 2.0 A X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases. Embo J 1988;7:2593e9.
212 [37] Turk BE, Huang LL, Piro ET, Cantley LC. Determination of protease cleavage site motifs using mixture-based oriented peptide libraries. Nat Biotechnol 2001;19:661e7. [38] Turk BE, Cantley LC. Using peptide libraries to identify optimal cleavage motifs for proteolytic enzymes. Methods 2004;32:398e405. [39] Janowski R, Kozak M, Abrahamson M, Grubb A, Jaskolski M. 3D domain-swapped human cystatin C with amyloidlike intermolecular beta-sheets. Proteins 2005;61:570e8. [40] Popovic T, Brzin J, Ritonja A, Turk V. Different forms of human cystatin C. Biol Chem Hoppe Seyler 1990;371: 575e80. [41] Agarwal R. Anti-inflammatory effects of short-term pioglitazone therapy in men with advanced diabetic
A.A. Aydemir-Koksoy nephropathy. Am J Physiol Renal Physiol 2006;290: F600e5. [42] Qing-Hua G, Ju-Ming L, Chang-Yu P, Zhao-Hui L, Xiao-Man Z, Yi-Ming M. The kidney expression of matrix metalloproteinase9 in the diabetic nephropathy of Kkay mice. J Diabetes Complications 2007. [43] Giedraitis V, Sundelof J, Irizarry MC, Garevik N, Hyman BT, Wahlund LO, et al. The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer’s disease. Neurosci Lett 2007;427:127e31. [44] Adair JC, Charlie J, Dencoff JE, Kaye JA, Quinn JF, Camicioli RM, et al. Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease. Stroke 2004;35:e159e62.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/bihy
A unifying hypothesis for explaining the mechanism of amyloid formation under conditions of increased oxidative stress Ayse Aslihan Aydemir-Koksoy* Department of Biophysics, School of Medicine, Ankara University, Sihhiye, 06100 Ankara, Turkey Received 25 July 2008; accepted 29 July 2008
KEYWORDS Cystatin c; Amyloid; Oxidative stres; Matrix metalloproteinases; Diabetes
Abstract Amyloid related organ dysfunction is a common feature of conditions associated with chronic oxidative injury such as diabetes, inflammation, neurodegenerative disorders, renal failure, and natural aging. Matrix metalloproteinases (MMPs) are a family of calcium and zinc-dependent endopeptidases comprised of 23 enzymes in the human. Among these, MMPs 2 and 9 are known as secretable forms, present in all body fluids and susceptible to activation by oxidants. Although MMPs are generally accepted and named for their effect on extracellular matrix turnover, their non-extracellular-matrix targets have emerged recently. Cystatin C (CysC) is a very potent inhibitor of cysteine proteinases, present in all body fluids. Its solubility is determined by its N-terminal sequence. CysC is known to polimerize and form fibrils and has been isolated from amyloids. The CysC isolated from amyloids is in the Nterminal truncated form. My hypothesis regarding amyloid formation is that CysC could be a substrate for MMPs 2 and 9, which upon cleaving the N-terminal off the CysC protein will render it insoluble and promote amyloid formation. Several in vitro studies have demonstrated degradation of CysC by MMPs. The implications of such a degradation in kidney glomerules (where the clearance of CysC occurs) could be of importance for understanding the mechanism of kidney failure e.g. in diabetes. This proposed mechanism for amyloid formation through degradation of CysC by MMPs, can be proposed for all cases of CysC related amyloid formation, such as those seen in cerebrovascular, cardiac and rheumatoid disorders. ª 2008 Elsevier Ltd. All rights reserved.
Introduction Chronic oxidative stress promotes amyloid formation [1e3]. Examples of amyloid related pathologies include type 2
* Tel.: þ90 312 310 3010x214; fax: þ90 312 310 6370. E-mail address: [email protected]
diabetes, Alzheimer’s disease, and senile cardiac amyloidosis [1,2,4]. In amyloid formation, the aggregate is formed by a change in the secondary-structure of the protein by formation of b-pleated-sheet, resulting in a less soluble conformation of the protein [3]. Cystatin C (CysC) belongs to the type 2 cystatin family of protease inhibitors. It is the dominating extracellular cysteine protease inhibitor of mammalians, produced at
1756-2392/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2008.07.005
210
A.A. Aydemir-Koksoy
a constant rate by the cells [5], with especially high concentrations in cerebrospinal fluid and synovial fluid [6]. The mature form of this secretable protein is 120 amino acids long, 13 kDa in size and its serum concentration is determined by glomerular filtration [5,7,8]. Enzyme binding by CysC requires an intact N-terminal and two beta hairpin loops [9]. Expression of a CysC variant, the L68Q, causes a disease named hereditary amyloid angiopathy leading to brain hemorrhage and death in early adulthood [10e12]. This variant of CysC is less stable than the wild-type and is susceptible to oligomerization and aggregation in vivo at body temperature through a mechanism called domain swapping [13e16]. Wild-type CysC can also give rise to amyloid formation over a very long time period as has been demonstrated for amyloid angiopathy of the elderly [17]. Human CysC isolated from the amyloid deposits is an Nterminal truncated from of the protein, 10 amino acids shorter than its original lengh [9,11,18]. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases which have a wide array of target proteins ranging from muscle myosin to serpins, along with extracellular matrix proteins [19,20]. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are known for functioning both intra- and extracellularly and have been reported to participate in the development of atherosclerosis, nephropathy and cardiomyopathy [21e25]. Both are produced as proenzymes and are activated by the ‘‘cysteine-switch’’ mechanism, which involves the cleavage of the N-terminal inhibitory peptide domain that results in dissociation of the cysteinyl sulphydryl and catalytic Znþ2 [26,27]. Other activation mechanisms which do not require the N-terminal cleavage of MMPs involve the oxidative modification of the cysteine thiol group within the propeptide domain [28,29]. A few papers and our unpublished observations have shown that under in vitro conditions CysC is a substrate for both MMP-2 and -9 [30,31].
Hypothesis In the light of the information given above I hypothesized that the activation of MMP-9 causes cleavage of N-terminal 11 aa residue from CysC which renders the protein to become insoluble and results in amyloid formation. Implications of this hypothesis brings explanation for the increased incidence amyloid formation in Alzheimer’s disease, pancreatic amyloidosis and nephropathy associated with diabetes.
Figure 1
Evaluation of the hypothesis in light of data from current literature CysC is the dominant inhibitor of cysteine proteases, especially cathepsin B, in the extracellular milieu [7,32]. The active form of CysC is a monomer of 120 amino acids long and forms 1:1 complexes with its target enzymes through the cysteine peptidase binding region which consists of N-terminal 2 b-hairpin loops [33,34]. This region contains the evolutionarily conserved Gly-11, Val-10, Lue-9 and Arg-8 residues which provide protein the ability to recognize and bind its targets with high affinity and specificity [35,36]. MMPs 2 and 9 are ubiquotosly expressed in human tissues and extracellular milieu. Data reported recently by Abdul-Hussien et al. [30], Overall and Dean [31] and my unpublished observations suggest that both MMP-2 and -9 degrade CysC in vitro. The analysis using LALIGN tool and the known cleavage sequences for MMP-2 and -9 from previously reported target proteins [20,37,38] gave me one sequence 70% homologous to MMP-9 cleavage sequences (Fig. 1). This putative cleavage site is within the first 12 residues of the N-terminal and the scissile bond is predicted to be between Arg-8 and Leu-9 (KPPR-LVGG). Analyzing for this cleavage site could be easily done in a lab with access to Edman degradation or mass spectrometry based protein sequence analyzers. A possible cleavage at this location could be enough to reduce the affinity of the protein for cathepsin B by 4000 fold as reported previously by Hall et al. [33]. This cleavage could also cause domain swapping between the N-terminal truncated cystatins, which will result in amyloid formation [39]. CysC amyloids isolated from patients with neurodegenerative diseases typically show the N-terminal truncation of the first 10 residues [18]. Current literature supports the co-localization of truncated CysC and increased MMP-9 expression. For example, presence of truncated CysC in urine samples isolated from patients with nephropathy was shown [40]. The increased expression of MMP-9 diabetic nephropathy has also been reported [41,42]. Truncated CysC and increased MMP-9 presence in cerebrospinal fluid are also reported for neurodegenerative disorders [43,44]. In this regard, should this hypothesis be correct, it could be suggested that therapies targeting control of MMP-9 activation, either directly (such as by doxycycline administration) or through reducing oxidative stress will be of therapeautic value for preventing amyloid formation.
MMP-9 cleavage motif for human CysC (X represents any amino acid and Xhy is a hydrophobic amino acid).
A unifying hypothesis for explaining the mechanism of amyloid formation
Conflict of interest The author has no conflict of interest.
Acknowledgements This study is granted by Ankara University Scientific Research Project BAP2003.08.09.120 and TUBA-GEBIP programme to reward successful young scientists.
References [1] Marzban L, Park K, Verchere CB. Islet amyloid polypeptide and type 2 diabetes. Exp Gerontol 2003;38:347e51. [2] Mancuso C, Scapagini G, Curro D, Giuffrida Stella AM, De Marco C, Butterfield DA, et al. Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front Biosci 2007;12:1107e23. [3] Monsellier E, Chiti F. Prevention of amyloid-like aggregation as a driving force of protein evolution. EMBO Rep 2007;8:737e42. [4] Dobson CM. Experimental investigation of protein folding and misfolding. Methods 2004;34:4e14. [5] Abrahamson M, Olafsson I, Palsdottir A, Ulvsback M, Lundwall A, Jensson O, et al. Structure and expression of the human cystatin C gene. Biochem J 1990;268:287e94. [6] Abrahamson M, Barrett AJ, Salvesen G, Grubb A. Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids. J Biol Chem 1986;261:11282e9. [7] Mussap M, Plebani M. Biochemistry and clinical role of human cystatin C. Crit Rev Clin Lab Sci 2004;41:467e550. [8] Tenstad O, Roald AB, Grubb A, Aukland K. Renal handling of radiolabelled human cystatin C in the rat. Scand J Clin Lab Invest 1996;56:409e14. [9] Janowski R, Abrahamson M, Grubb A, Jaskolski M. Domain swapping in N-truncated human cystatin C. J Mol Biol 2004; 341:151e60. [10] Olafsson I, Grubb A. Hereditary cystatin C amyloid angiopathy. Amyloid 2000;7:70e9. [11] Ghiso J, Jensson O, Frangione B. Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). Proc Natl Acad Sci U S A 1986;83:2974e8. [12] Jensson O, Palsdottir A, Thorsteinsson L, Arnason A, Abrahamson M, Olafsson I, et al. Cystatin C mutation causing amyloid angiopathy and brain hemorrhage. Biol Chem Hoppe Seyler 1990;371(Suppl):229e32. [13] Jaskolski M. 3D domain swapping, protein oligomerization, and amyloid formation. Acta Biochim Pol 2001;48:807e27. [14] Janowski R, Kozak M, Jankowska E, Grzonka Z, Grubb A, Abrahamson M, et al. Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. Nat Struct Biol 2001;8:316e20. [15] Nilsson M, Wang X, Rodziewicz-Motowidlo S, Janowski R, Lindstrom V, Onnerfjord P, et al. Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C: use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C. J Biol Chem 2004;279:24236e45. [16] Wahlbom M, Wang X, Lindstrom V, Carlemalm E, Jaskolski M, Grubb A. Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping. J Biol Chem 2007; 282:18318e26. [17] Yamada M. Cerebral amyloid angiopathy: an overview. Neuropathology 2000;20:8e22.
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[18] Olafsson I, Gudmundsson G, Abrahamson M, Jensson O, Grubb A. The amino terminal portion of cerebrospinal fluid cystatin C in hereditary cystatin C amyloid angiopathy is not truncated: direct sequence analysis from agarose gel electropherograms. Scand J Clin Lab Invest 1990;50:85e93. [19] Chen EI, Li W, Godzik A, Howard EW, Smith JW. A residue in the S2 subsite controls substrate selectivity of matrix metalloproteinase-2 and matrix metalloproteinase-9. J Biol Chem 2003;278:17158e63. [20] Chen EI, Kridel SJ, Howard EW, Li W, Godzik A, Smith JW. A unique substrate recognition profile for matrix metalloproteinase-2. J Biol Chem 2002;277:4485e91. [21] Catania JM, Chen G, Parrish AR. Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol Renal Physiol 2007;292:F905e11. [22] Schulz R. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol 2007;47:211e42. [23] Thrailkill KM, Bunn RC, Moreau CS, Cockrell GE, Simpson PM, Coleman HN, et al. Matrix metalloproteinase-2 dysregulation in type 1 diabetes. Diabetes Care 2007;30:2321e6. [24] Sanders JS, Huitema MG, Hanemaaijer R, van Goor H, Kallenberg CG, Stegeman CA. Urinary matrix metalloproteinases reflect renal damage in anti-neutrophil cytoplasm autoantibody-associated vasculitis. Am J Physiol Renal Physiol 2007;293:F1927e34. [25] Rysz J, Banach M, Stolarek RA, Pasnik J, Cialkowska-Rysz A, Koktysz R, et al. Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy. J Nephrol 2007;20:444e52. [26] Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 1990;87:5578e82. [27] Fridman R, Toth M, Pena D, Mobashery S. Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res 1995;55:2548e55. [28] Okamoto T, Akaike T, Sawa T, Miyamoto Y, van der Vliet A, Maeda H. Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem 2001;276:29596e602. [29] Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, et al. Snitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 2002;297:1186e90. [30] Abdul-Hussien H, Soekhoe RG, Weber E, von der Thusen JH, Kleemann R, Mulder A, et al. Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases. Am J Pathol 2007;170:809e17. [31] Overall CM, Dean RA. Degradomics: systems biology of the protease web. Pleiotropic roles of MMPs in cancer. Cancer Metastasis Rev 2006;25:69e75. [32] Turk V, Bode W. The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett 1991;285:213e9. [33] Hall A, Hakansson K, Mason RW, Grubb A, Abrahamson M. Structural basis for the biological specificity of cystatin C. Identification of leucine 9 in the N-terminal binding region as a selectivity-conferring residue in the inhibition of mammalian cysteine peptidases. J Biol Chem 1995;270:5115e21. [34] Abrahamson M, Alvarez-Fernandez M, Nathanson CM. Cystatins. Biochem Soc Symp 2003:179e99. [35] Abrahamson M, Buttle DJ, Mason RW, Hansson H, Grubb A, Lilja H, et al. Regulation of cystatin C activity by serine proteinases. Biomed Biochim Acta 1991;50:587e93. [36] Bode W, Engh R, Musil D, Thiele U, Huber R, Karshikov A, et al. The 2.0 A X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases. Embo J 1988;7:2593e9.
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