Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1: FUNCTIONAL INTERACTIONS BETWEEN THE KUNITZ-TYPE INHIBITOR DOMAIN-1 AND THE NEIGHBORING POLYCYSTIC KIDNEY DISEASE-LIKE DOMAIN

被引:17
作者
Hong, Zebin [1 ]
De Meulemeester, Laura [1 ]
Jacobi, Annemarie [1 ]
Pedersen, Jan Skov [2 ,3 ]
Morth, J. Preben [4 ]
Andreasen, Peter A. [1 ]
Jensen, Jan K. [1 ]
机构
[1] Aarhus Univ, Dept Mol Biol & Genet, Danish Chinese Ctr Proteases & Canc, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark
[2] Aarhus Univ, Dept Chem, DK-8000 Aarhus C, Denmark
[3] Aarhus Univ, iNANO Interdisciplinary Nanosci Ctr, DK-8000 Aarhus C, Denmark
[4] Univ Oslo, NCMM, NO-0316 Oslo, Norway
关键词
cell surface protein; inhibition mechanism; protease inhibitor; protein-protein interaction; tertiary structure; multidomain protein; SERINE-PROTEASE INHIBITOR; MATRIPTASE; SCATTERING; HAI-1; SPECIFICITY; ICHTHYOSIS; SUBSTRATE; INSIGHTS; CLEAVAGE; COMPLEX;
D O I
10.1074/jbc.M115.707240
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a type I transmembrane protein and inhibitor of several serine proteases, including hepatocyte growth factor activator and matriptase. The protein is essential for development as knock-out mice die in utero due to placental defects caused by misregulated extracellular proteolysis. HAI-1 contains two Kunitz-type inhibitor domains (Kunitz), which are generally thought of as a functionally self-contained protease inhibitor unit. This is not the case for HAI-1, where our results reveal how interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. Here we present an x-ray crystal structure of an HAI-1 fragment covering the internal domain and Kunitz-1. The structure reveals not only that the previously uncharacterized internal domain is a member of the polycystic kidney disease domain family but also how the two domains engage in interdomain interactions. Supported by solution small angle x-ray scattering and a combination of site-directed mutagenesis and functional assays, we show that interdomain interactions not only stabilize the fold of the internal domain but also stimulate the inhibitory activity of Kunitz-1. By completing our structural characterization of the previously unknown N-terminal region of HAI-1, we provide new insight into the interplay between tertiary structure and the inhibitory activity of a multidomain protease inhibitor. We propose a previously unseen mechanism by which the association of an auxiliary domain stimulates the inhibitory activity of a Kunitz-type inhibitor (i.e. the first structure of an intramolecular interaction between a Kunitz and another domain).
引用
收藏
页码:14340 / 14355
页数:16
相关论文
共 54 条
[1]   PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution [J].
Adams, Paul D. ;
Afonine, Pavel V. ;
Bunkoczi, Gabor ;
Chen, Vincent B. ;
Davis, Ian W. ;
Echols, Nathaniel ;
Headd, Jeffrey J. ;
Hung, Li-Wei ;
Kapral, Gary J. ;
Grosse-Kunstleve, Ralf W. ;
McCoy, Airlie J. ;
Moriarty, Nigel W. ;
Oeffner, Robert ;
Read, Randy J. ;
Richardson, David C. ;
Richardson, Jane S. ;
Terwilliger, Thomas C. ;
Zwart, Peter H. .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2010, 66 :213-221
[2]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[3]   A homolog of Kunitz-type serine protease inhibitor from rock bream, Oplegnathus fasciatus: Molecular insights and transcriptional modulation in response to microbial and PAMP stimulation, and tissue injury [J].
Bathige, S. D. N. K. ;
Umasuthan, Navaneethaiyer ;
Godahewa, G. I. ;
Jayasinghe, J. D. H. E. ;
Whang, Ilson ;
Noh, Jae Koo ;
Lee, Jehee .
FISH & SHELLFISH IMMUNOLOGY, 2015, 46 (02) :285-291
[4]   The structure of a PKD domain from polycystin-1: Implications for polycystic kidney disease [J].
Bycroft, M ;
Bateman, A ;
Clarke, J ;
Hamill, SJ ;
Sandford, R ;
Thomas, RL ;
Chothia, C .
EMBO JOURNAL, 1999, 18 (02) :297-305
[5]  
Copeland R. A., 2000, ENZYMES PRACTICAL IN
[6]   Functional characterization of Kunitz domains in hepatocyte growth factor activator inhibitor type 1 [J].
Denda, K ;
Shimomura, T ;
Kawaguchi, T ;
Miyazawa, K ;
Kitamura, N .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (16) :14053-14059
[7]   Cleavage of hepatocyte growth factor activator inhibitor-1 by membrane-type MMP-1 activates matriptase [J].
Domoto, Takahiro ;
Takino, Takahisa ;
Guo, Luyang ;
Sato, Hiroshi .
CANCER SCIENCE, 2012, 103 (03) :448-454
[8]   Features and development of Coot [J].
Emsley, P. ;
Lohkamp, B. ;
Scott, W. G. ;
Cowtan, K. .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2010, 66 :486-501
[9]   Identification of hepatocyte growth factor activator inhibitor-1B as a potential physiological inhibitor of prostasin [J].
Fan, B ;
Wu, TD ;
Li, W ;
Kirchhofer, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (41) :34513-34520
[10]   Hepatocyte growth factor activator inhibitor-1 (HAI-1) is essential for the integrity of basement membranes in the developing placental labyrinth [J].
Fan, Bin ;
Brennan, Jane ;
Grant, Deanna ;
Peale, Franklin ;
Rangell, Linda ;
Kirchhofer, Daniel .
DEVELOPMENTAL BIOLOGY, 2007, 303 (01) :222-230