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J. Biol. Chem., Vol. 281, Issue 44, 33566-33576, November 3, 2006

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Human Pancreatitis-associated Protein Forms Fibrillar Aggregates with a Native-like Conformation^*

Meng-Ru Ho, Yuan-Chao Lou, Wen-Chang Lin, Ping-Chiang Lyu, Wei-Ning Huang^¶, and Chinpan Chen¹

From the Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, the Institute of Bioinformatics and Structural Biology, College of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan, and the ^¶Department of Biotechnology, Yuanpei Institute of Science and Technology, Hsinchu 300, Taiwan

Human pancreatitis-associated protein was identified in pathognomonic lesions of Alzheimer disease, a disease characterized by the presence of filamentous protein aggregates. Here, we showed that at physiological pH, human pancreatitis-associated protein forms non-Congo Red-binding, proteinase K-resistant fibrillar aggregates with diameters from 6 up to as large as 68 nm. Interestingly, circular dichroism and Fourier transform infrared spectra showed that, unlike typical amyloid fibrils, which have a cross--sheet structure, these aggregates have a very similar secondary structure to that of the native protein, which is composed of two -helices and eight -strands, as determined by NMR techniques. Surface structure analysis showed that the positively charged and negatively charged residues were clustered on opposite sides, and strong electrostatic interactions between molecules were therefore very likely, which was confirmed by cross-linking experiments. In addition, several hydrophobic residues were found to constitute a continuous hydrophobic surface. These results and protein aggregation prediction using the TANGO algorithm led us to synthesize peptide Thr⁸⁴ to Ser¹¹⁶, which, very interestingly, was found to form amyloid-like fibrils with a cross- structure. Thus, our data suggested that human pancreatitis-associated protein fibrillization is initiated by protein aggregation primarily because of electrostatic interactions, and the loop from residues 84 to 116 may play an important role in the formation of fibrillar aggregates with a native-like conformation.

Received for publication, May 11, 2006 , and in revised form, August 8, 2006.

The atomic coordinates and structure factors (code 2GO0) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Academia Sinica and National Science Council Grant NSC 94-2311-B-001-067 (to C. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Section 2, Nankang, Taipei 115, Taiwan. Tel.: 886-2-2652-3035; Fax: 886-2-2788-7641; E-mail: bmchinp{at}ibms.sinica.edu.tw.

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