Adrenoleukodystrophy: Structure and Function of ALDP, and Intracellular Behavior of Mutant ALDP with Naturally Occurring Missense Mutations

• TAKAHASHI Norimasa

  Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

• MORITA Masashi

  Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

• IMANAKA Tsuneo

  Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

Bibliographic Information

Other Title

• 副腎白質ジストロフィー:ALDPの構造・機能とミスセンス変異ALDPの細胞内動態
• 誌上シンポジウム 副腎白質ジストロフィー:ALDPの構造・機能とミスセンス変異ALDPの細胞内動態
• シジョウ シンポジウム フクジン ハクシツ ジストロフィー ALDP ノ コウゾウ キノウ ト ミスセンス ヘンイ ALDP ノ サイボウ ナイ ドウタイ

Abstract

  Adrenoleukodystrophy (ALD) is an inherited disorder characterized by progressive demyelination of the central nervous system and adrenal dysfunction. The biochemical characterization is based on the accumulation of pathgnomonic amounts of saturated very long-chain fatty acid (VLCFA; C>22) in all tissues, including the brain white matter, adrenal glands, and skin fibroblasts, of the patients. The accumulation of VLCFA in ALD is linked to a mutation in the ALD (ABCD1) gene, an ABC subfamily D member. The ALD gene product, so-called ALDP (ABCD1), is thought to be involved in the transport of VLCFA or VLCFA-CoA into the peroxisomes. ALDP is a half-sized peroxisomal ABC protein and it has 745 amino acids in humans. ALDP is thought to be synthesized on free polysomes, posttranslationally transported to peroxisomes, and inserted into the membranes. During this process, ALDP interacts with Pex19p, a chaperone-like protein for intracellular trafficking of peroxisomal membrane protein (PMP), the complex targets Pex3p on the peroxisomal membranes, and ALDP is inserted into the membranes. After integration into the membranes, ALDP is thought to form mainly homodimers. Here, we chose nine arbitrary mutations of human ALDP with naturally occurring missense mutations and examined the intracellular behavior of their ALDPs. We found that mutant ALDP (S606L, R617H, and H667D) was degraded together with wild-type ALDP by proteasomes. These results suggest that the complex of mutant and wild-type ALDP is recognized as misfolded proteins and degraded by the protein quality control system associated with proteasomes. Further, we found fragmentation of mutant ALDP (R104C) on peroxisomes and it was not inhibited by proteasomes inhibitors, suggesting that an additional protease(s) is also involved in the quality control of mutant ALDP. In addition, mutation of ALDP (Y174C) suggests that a loop between transmembrane domains 2 and 3 is important for the targeting of ALDP to peroxisomes.<br>

Journal

• YAKUGAKU ZASSHI

  YAKUGAKU ZASSHI 127 (1), 163-172, 2007-01-01

  The Pharmaceutical Society of Japan

Keywords

• adrenoleukodystrophy
• ALDP (ABCD1)
• missense mutation
• targeting
• degradation
• proteasome

Details

• CRID: 1390001206129551616
• NII Article ID: 110006155022
• NII Book ID: AN00284903
• DOI: 10.1248/yakushi.127.163
• COI: 1:CAS:528:DC%2BD2sXktVSltr4%3D
• ISSN: 13475231
• ISSN: 00316903
• NDL BIB ID: 8632183
• PubMed: 17202797
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I8632183
• Web Site: https://www.jstage.jst.go.jp/article/yakushi/127/1/127_1_163/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2007160429
• Text Lang: ja
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed