HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 45, 34503-34514, November 10, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/45/34503    most recent M600071200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsumura, Y. Articles by Inagaki, N. Search for Related Content PubMed PubMed Citation Articles by Matsumura, Y. Articles by Inagaki, N. Social Bookmarking                      What's this?

Characterization and Classification of ATP-binding Cassette Transporter ABCA3 Mutants in Fatal Surfactant Deficiency^*

Yoshihiro Matsumura, Nobuhiro Ban, Kazumitsu Ueda^¶, and Nobuya Inagaki¹

From the Department of Physiology, Akita University School of Medicine, Akita 010-8543, ^¶Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, and the Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University and CREST of Japan Science and Technology Corporation, Kyoto 606-8507, Japan

The ATP-binding cassette transporter ABCA3 is expressed predominantly at the limiting membrane of the lamellar bodies in lung alveolar type II cells. Recent study has shown that mutation of the ABCA3 gene causes fatal surfactant deficiency in newborns. In this study, we investigated in HEK293 cells the intracellular localization and N-glycosylation of the ABCA3 mutants so far identified in fatal surfactant deficiency patients. Green fluorescent protein-tagged L101P, L982P, L1553P, Q1591P, and Ins1518fs/ter1519 mutant proteins remained localized in the endoplasmic reticulum, and processing of oligosaccharide was impaired, whereas wild-type and N568D, G1221S, and L1580P mutant ABCA3 proteins trafficked to the LAMP3-positive intracellular vesicle, accompanied by processing of oligosaccharide from high mannose type to complex type. Vanadate-induced nucleotide trapping and ATP-binding analyses showed that ATP hydrolysis activity was dramatically decreased in the N568D, G1221S, and L1580P mutants, accompanied by a moderate decrease in ATP binding in N568D and L1580P mutants but not in the G1221S mutant, compared with the wild-type ABCA3 protein. In addition, mutational analyses of the Gly-1221 residue in the 11th transmembrane segment and the Leu-1580 residue in the cytoplasmic tail, and homology modeling of nucleotide binding domain 2 demonstrate the significance of these residues for ATP hydrolysis and suggest a mechanism for impaired ATP hydrolysis in G1221S and L1580P mutants. Thus, surfactant deficiency because of ABCA3 gene mutation may be classified into two categories as follows: abnormal intracellular localization (type I) and normal intracellular localization with decreased ATP binding and/or ATP hydrolysis of the ABCA3 protein (type II). These distinct pathophysiologies may reflect both the severity and effective therapy for surfactant deficiency.

Received for publication, January 4, 2006 , and in revised form, September 5, 2006.

^* This work was supported by Scientific Research Grants and a Grant-in-aid for Creative Scientific Research 15GS0301 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 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: Dept. of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: 81-75-751-3562; Fax: 81-75-771-6601; E-mail: inagaki{at}metab.kuhp.kyoto-u.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				W. A. Gower, S. E. Wert, and L. M. Nogee Inherited Surfactant Disorders NeoReviews, October 1, 2008; 9(10): e458 - e467. [Abstract] [Full Text] [PDF]

				Y. Matsumura, N. Ban, and N. Inagaki Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L698 - L707. [Abstract] [Full Text] [PDF]

				L. R. Young, L. M. Nogee, B. Barnett, R. J. Panos, T. V. Colby, and G. H. Deutsch Usual Interstitial Pneumonia in an Adolescent With ABCA3 Mutations Chest, July 1, 2008; 134(1): 192 - 195. [Abstract] [Full Text] [PDF]

				A. V. Andreeva, M. A. Kutuzov, and T. A. Voyno-Yasenetskaya Regulation of surfactant secretion in alveolar type II cells Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L259 - L271. [Abstract] [Full Text] [PDF]

				A. Bush Update in Pediatric Lung Disease 2006 Am. J. Respir. Crit. Care Med., March 15, 2007; 175(6): 532 - 540. [Full Text] [PDF]

				M. L. Fitzgerald, R. Xavier, K. J. Haley, R. Welti, J. L. Goss, C. E. Brown, D. Z. Zhuang, S. A. Bell, N. Lu, M. Mckee, et al. ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol J. Lipid Res., March 1, 2007; 48(3): 621 - 632. [Abstract] [Full Text] [PDF]