A decade ago, motif at N-terminus with eight-cysteines (MANEC) was defined as a new protein domain family. This domain is found exclusively at the N-terminus of >400 multi-domain type-1 transmembrane proteins from animals. Despite the large number of MANEC-containing proteins, only one has been characterized at the protein level: hepatocyte growth factor activator inhibitor-1 (HAI-1). HAI-1 is an essential protein, as knockout mice die in utero due to placental defects. HAI-1 is an inhibitor of matriptase, hepsin and hepatocyte growth factor (HGF) activator, all serine proteases with important roles in epithelial development, cell growth and homoeostasis. Dysregulation of these proteases has been causatively implicated in pathological conditions such as skin diseases and cancer. Detailed functional understanding of HAI-1 and other MANEC-containing proteins is hampered by the lack of structural information on MANEC. Although many MANEC sequences exist, sequence-based database searches fail to predict structural homology. In the present paper, we present the NMR solution structure of the MANEC domain from HAI-1, the first three-dimensional (3D) structure from the MANEC domain family. Unexpectedly, MANEC is a new subclass of the PAN/apple domain family, with its own unifying features, such as two additional disulfide bonds, two extended loop regions and additional α-helical elements. As shown for other PAN/apple domain-containing proteins, we propose a similar active role of the MANEC domain in intramolecular and intermolecular interactions. The structure provides a tool for the further elucidation of HAI-1 function as well as a reference for the study of other MANEC-containing proteins.
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Research Article|
February 20 2015
The solution structure of the MANEC-type domain from hepatocyte growth factor activator inhibitor-1 reveals an unexpected PAN/apple domain-type fold
Zebin Hong;
Zebin Hong
*Department of Molecular Biology and Genetics, Danish-Chinese Centre for Proteases and Cancer, Aarhus University, 8000 Aarhus C, Denmark
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Michal Nowakowski;
Michal Nowakowski
†Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 00-927 Warsaw, Poland
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Chris Spronk;
Chris Spronk
‡Spronk NMR, LT-01104, Lithuania
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Steen V. Petersen;
Steen V. Petersen
§Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark
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Peter A. Andreasen;
Peter A. Andreasen
*Department of Molecular Biology and Genetics, Danish-Chinese Centre for Proteases and Cancer, Aarhus University, 8000 Aarhus C, Denmark
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Wiktor Koźmiński;
Wiktor Koźmiński
†Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 00-927 Warsaw, Poland
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Frans A.A. Mulder;
Frans A.A. Mulder
║Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark
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Jan K. Jensen
Jan K. Jensen
1
*Department of Molecular Biology and Genetics, Danish-Chinese Centre for Proteases and Cancer, Aarhus University, 8000 Aarhus C, Denmark
1To whom correspondence should be addressed (email jkj@mb.au.dk).
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Publisher: Portland Press Ltd
Received:
October 06 2014
Revision Received:
December 12 2014
Accepted:
December 16 2014
Accepted Manuscript online:
December 16 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 466 (2): 299–309.
Article history
Received:
October 06 2014
Revision Received:
December 12 2014
Accepted:
December 16 2014
Accepted Manuscript online:
December 16 2014
Citation
Zebin Hong, Michal Nowakowski, Chris Spronk, Steen V. Petersen, Peter A. Andreasen, Wiktor Koźmiński, Frans A.A. Mulder, Jan K. Jensen; The solution structure of the MANEC-type domain from hepatocyte growth factor activator inhibitor-1 reveals an unexpected PAN/apple domain-type fold. Biochem J 1 March 2015; 466 (2): 299–309. doi: https://doi.org/10.1042/BJ20141236
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