Cystatin structure

To this list of protein misfolding diseases can be added rare familial amyloidoses in which the mutated proteins have the classic amyloid fibril congophilic birefringence and cross-(3-sheet structure (Table 3). Many of these deposits have an impact on the central nervous system (TTR, cystatin, lysozyme) as well as on other organ systems. A newly described disease, familial British dementia, is associated with the deposition of Abri, a 34 amino acid, 4 kDa peptide cleaved from a 277 amino acid precursor sequence, the last 10 amino acids of which are not normally translated [52]. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is... 

Two models have been proposed for how this dimeric structure may relate to the structure of cystatin C in the fibril. The first (Janowski et at, 2001) proposes that run-away domain swapping (like that shown in Fig. 11C) can account for the assembly and stability of the fibril. In this model, one monomer would swap /(I-a 1-/12 into a second monomer, the second would swap its /(I-a 1-/12 into a third, and so on. The second model (Staniforth et al., 2001) proposes a direct stacking of domain-swapped dimers, where /i5 of each subunit of the dimer would interact with /(I of a subunit of the adjacent dimer. In this way, the dimers would stack to form continuous /1-sheets. Both models arrange the /(-sheets parallel to the fibril axis with component /(-strands perpendicular to the axis, as in a cross-/ structure, although no diffraction pattern has been reported for cystatin fibrils. 

Staniforth, R. A., Giannini, S., Higgins, L. D., Conroy, M. J., Hounslow, A. M.,Jerala, R., Craven, C. J., and Waltho, J. P. (2001). Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily. EMBO J. 20, 4774-4781. 

Structure of Human Cystatin C and Its Concentration in Body Fluids. 72... 

Fig. 1. Amino acid sequence and schematic structure of human cystatin C. The shaded area marks the inhibitory site for papain-like cysteine proteases, which does not overlap with the inhibitory site for mammalian legumains comprising, inter alia, the Asn39 residue. The arrow indicates the Leu68 residue, which is replaced with a Gin residue in the cerebral hemorrhage producing cystatin C variant. The asterisk marks the Pro3 residue, which is partly hydroxylated.

The three-dimensional structure of cystatin C is not yet determined, although some crystallographic data are available (K8), but it can be presumed that it is similar to that described for the homologous protein chicken cystatin (B19) and this has, at least partially, been confirmed by NMR studies (El). A schematic structure for human cystatin C is given in Fig. 1. 

B19. Bode, W., Engh, R., Musil, D., Thiele, U., Huber, R., etal, The 2.0 A X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases. Embo. 

F2. Freije, J. P., Abrahamson, M., Olafsson, I., Velasco, G., Grubb, A., and Lopez-Otin, C., Structure and expression of the gene encoding cystatin D, a novel human cysteine proteinase inhibitor. J. Biol. Chem. 266(30), 20538-20543 (1991). 

H6. Hall, A., Hakansson, K., Mason, R. W., Grubb, A., and 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. 270(10), 5115-5121 (1995). 

N3. Ni, J., Abrahamson, M., Zhang, M., Fernandez, MA., Grubb A., et al., Cystatin E is a novel human cysteine proteinase inhibitor with structural resemblance to family 2 cystatins. J. Biol. Chem. 272(16) 10853-10858 (1997). 

Salvesen, G., Parkes, C., Abrahamson, M., Grubb, A., and Barrett, A. J., Human low-Mr Kinino-gen contains three copies of a cystatin sequence that are divergent in structure and in inhibitory activity for cysteine proteinases. Biochem. J. 234(2), 129 131 (1986). 

Staniforth RA, et al. Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily. EMBO J. 2001 20 4774-4781. 

Flerget-Rosenthal S, van Wijk JA, Brocker-Preuss M, Bokenkamp A. Increased urinary cystatin C reflects structural and functional renal tubular impairment independent of glomerular filtration rate. Clin Biochem 2007 27 April [Epub ahead of print].This study provides evidence for urinary cystatin C as a biomarker for tubular injury. 

Cystatins, a human superfamily of cysteine peptidase inhibitors. They are tight-binding reversible inhibitors of many cysteine proteases, and are not capable of inhibiting other proteases. Members of this superfamily contain at least two intrachain disulfide bonds and an a-helical structure over a distance of about 100 aa. This superfamily comprises (i) Family 1 (intracellular cystatins) cystatin A and cystatin B (ii) Family 2 (extracellular and/or transcellular cystatins) cystatin G, cystatin D, cystatin E, cystatin F, cystatin G, cystatin S, cystatin SA and cystatin SN and (iii) Family 3 (intravascular cystatins) LMW-kininogen and HMW-kininogen [A. J. Barret, Trends Biol. Sci. 1987, 12, 193 S. Nagpal et al., J. Invest. Dermatol. 1997, 109, 91 M. Zanatti,... 

Juszczyk P., Paraschiv G., Szymanska A., Kolodziejczyk A.S., Rodziewicz-Motowidlo S., Grzonka Z., Przybylski M. (2009) Binding epitopes and interaction structure of the neuroprotective protease inhibitor cystatin C with beta-amyloid revealed by proteolytic excision mass spectrometry and molecular docking simulation. J Med Chem, 52 2420-8. 

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